ArticlePDF AvailableLiterature Review

Critical thinking of Alzheimer's transgenic mouse model: current research and future perspective

July 2023
Science China. Life sciences 66(12)

DOI:10.1007/s11427-022-2357-x

Authors:

Meina Quan

Xuanwu Hospital, Capital Medical University

Wei Wang

National Formosa University

Show all 7 authorsHide

Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease (AD). AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD. Each transgenic model has its unique behavioral and pathological features. This review summarizes the research progress of transgenic mouse models, and their progress in the unique mechanism of amyloid-β oligomers, including the first transgenic mouse model built in China based on a single gene mutation (PSEN1 V97L) found in Chinese familial AD. We further summarized the preclinical findings of drugs using the models, and their future application in exploring the upstream mechanisms and multitarget drug development in AD.

Content uploaded by Meina Quan

Content may be subject to copyright.

•REVIEW•https://doi.org/10.1007/s11427-022-2357-x

...........................................................................................................

Critical thinking of Alzheimer’s transgenic mouse model: current

research and future perspective

Xinyue Li1†, Meina Quan1,2†, Yiping Wei1, Wei Wang1,2, Lingzhi Xu1,

Qi Wang1,2 & Jianping Jia1,2,3,4,5,6*

1Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University,

Beijing 100053, China;

2National Medical Center for Neurological Diseases and National Clinical Research Center for Geriatric Diseases, Beijing 100053, China;

3Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing 100053, China;

4Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing 100053, China;

5Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical

University, Beijing 100053, China;

6Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, China

Received December 22, 2022; accepted April 23, 2023; published online July 17, 2023

Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer’s Disease (AD). AD

models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD. Each

transgenic model has its unique behavioral and pathological features. This review summarizes the research progress of transgenic

mouse models, and their progress in the unique mechanism of amyloid-β oligomers, including the first transgenic mouse model

built in China based on a single gene mutation (PSEN1 V97L) found in Chinese familial AD. We further summarized the

preclinical findings of drugs using the models, and their future application in exploring the upstream mechanisms and multi-

target drug development in AD.

Alzheimer’s disease, transgenic mouse model, amyloid-β oligomers, multi-target therapy

Citation: Li, X., Quan, M., Wei, Y., Wang, W., Xu, L., Wang, Q., and Jia, J. (2023). Critical thinking of Alzheimer’s transgenic mouse model: current research

and future perspective. Sci China Life Sci 66, https://doi.org/10.1007/s11427-022-2357-x

Introduction

Current animal models for Alzheimer’s disease (AD) include

intermediate state animal vectors such as C.elegans, fruit fly

and zebrafish, high level models such as rodents and non-

human primates (Drummond and Wisniewski, 2017). There

are several methods for AD modeling, such as spontaneous

aging, physical or chemical lesion, and gene modification,

which include transgenosis and gene editing (Drummond

and Wisniewski, 2017;Götz et al., 2018;Zhang et al., 2020).

AD transgenic (Tg) Drosophila models can show patholo-

gical changes such as synaptic degeneration, axonal changes,

and apoptosis, and can shorten experimental cycle (Guna-

wardena and Goldstein, 2001). However, the lower order

animal models have limitations such as great distance from

human physiology, lack of genetic homology with humans,

lack of amyloid-β (Aβ), complexity in nervous system, and

behaviors seen in human (Alexander et al., 2014;Fernandez-

Funez et al., 2015). Non-human primates have the limitations

of long lifespan, high price, immature cognitive behavioral

paradigm, rare tauopathy and ethical concerns for research

studies (Drummond and Wisniewski, 2017;Heuer et al.,

SCIENCE CHINA

Life Sciences

†Contributed equally to this work

*Corresponding author (email: jiajp@vip.126.com)

2012;Perez et al., 2013). The most frequently used animal

models are rodents, especially transgenic models. Though

transgenic rat models of AD have also been developed, they

are not as well characterized as mouse models, and amyloid

plaque expression is at lower levels than in transgenic mice

(Cohen et al., 2013;Leon et al., 2010;Pang et al., 2022).

Mice have the advantages of small size, short reproductive

cycle, mature gene modification technology, high homology

with human genes and high-level neural activities, thus are

suitable for understanding AD pathogenesis and develop-

ment of candidate AD therapies (Hafezparast et al., 2002).

There are three methods to construct transgenic mouse

models of AD: random transgenic, CRISPR/Cas9 and em-

bryonic stem cell targeting. Each of the three technologies

has its advantages and disadvantages. Random transgenic

technology is to randomly integrate foreign genes into mouse

chromosomes to obtain randomly inserted transgenic mice

(Jaenisch and Mintz, 1974;Oakley et al., 2006). Generally,

the founder (F0) mice obtained need to be bred in-

dependently, and backcrossed with wild type (WT) mice for

more than two generations to detect the expression of foreign

genes, in order to screen out mouse strains that meet the

experimental requirements. The advantage of this method is

that mice with multiple expression levels of target genes can

be obtained. The disadvantage is that the reproduction work

is cumbersome and not sure to obtain an ideal model of

foreign gene expression, and there is a risk that the genetic

information of the mouse itself might be destroyed. CRISPR/

Cas9 introduces the target DNA fragment through homo-

logous recombination with Cas9 protein and guide RNA as

the core, then gets the exogenous gene knock-in (KI) or gene

editing mice (Gaj et al., 2013;Li et al., 2013;Shen et al.,

2013). Embryonic stem cell targeting technology carries out

DNA homologous recombination in mouse embryonic stem

cells to obtain gene KI or gene editing mice (Thomas and

Capecchi, 1987). Both CRISPR/Cas9 and embryonic stem

cell targeting can obtain mouse humanization, gene knock-

out (KO) and point mutation models. CRISPR/Cas9 has a

short cycle and low cost, but there is a risk of missing target

and it is not suitable for complex genetic transformation.

Embryonic stem cell targeting technology has a long cycle

and high cost, but there is no risk of missing target and it is

suitable for complex gene transformation.

The first AD transgenic mouse model was generated in the

1990s, based on overexpression of human amyloid precursor

protein (APP) with familial AD (FAD) mutation (Games et

al., 1995). Thereafter, more and more transgenic models

were generated, including single transgenic and multiple

transgenic models (Borchelt et al., 1997;Mucke et al., 2000;

Scearce-Levie et al., 2020;Sturchler-Pierrat et al., 1997).

Transgenic mouse models have some common features as

well as heterogeneities. The most commonly used mouse

models carry two or more mutations, and have prominent

pathological characteristics and early onset age (Mullane and

Williams, 2019;Rao and Yamada, 2021). Different mutation

sites have different pathogenic functions for AD (Qiu et al.,

2020;Shen et al., 2019). Neuropsychological and imaging

studies also found that APP mutation, PSEN1 mutation and

APOE affect cognitive phenotypes and imaging biomarkers

in a different way (Almkvist et al., 2019;Quan et al., 2020;

Wong et al., 2020). As a result, the mechanisms based on

each model may only be a subtype of AD pathogenesis, not

as a whole.

According to AlzForum (https://www.alzforum.org/re-

search-models/alzheimers-disease), there are 197 AD mouse

models. This review intends to review the current research

findings and progress on transgenic mouse models, including

three major pathogenic genes (APP,PSEN1,PSEN2), AD

risk genes and some AD-related genes such as MAPT gene.

The usage of these mouse models in drug development stu-

dies is also reviewed. This review aims to deepen our un-

derstanding of AD pathogenesis and shed light on the future

applications of transgenic mice in drug development.

Comparisons between single-transgenic mouse

models

The pathological, electrophysiological, and cognitive fea-

tures were compared between single mutation transgenic

mouse models reported in AlzForum and the literature, and

the timing of each feature was also summarized. Most AD

single transgenic mouse models are constructed with APP,

PSEN1 and MAPT gene mutations. Two PSEN2 models were

found in AlzForum, but they lack pathological evidence

(Hwang et al., 2002;Richards et al., 2003).

PSEN1 single-transgenic mouse models

Seven mouse models carrying a single mutation of PSEN1

with more than one pathological change or cognitive im-

pairments are summarized in Table 1 (Barrow et al., 2000;

Begley et al., 1999;Duff et al., 1996;Guo et al., 1999;

Holcomb et al., 1998;Lalonde and Strazielle, 2005;Nakano

et al., 1999;Schneider et al., 2001;Tanemura et al., 2006;

Wang et al., 2004;Wang et al., 2016;Wang et al., 2012;Wen

et al., 2004;Wen et al., 2002;Zhang et al., 2014;Zufferey et

al., 2013). We can see that PS1(I213T) KI, PS1(M146L),

PS1(M146V), PS1(P117L), and PS1V97L Tg mice showed

elevated Aβ42 level, and Aβ plaques were not seen in any

PSENs single transgenic models (Barrow et al., 2000;Begley

et al., 1999;Nakano et al., 1999;Wen et al., 2004;Zhang et

al., 2014). Only PS1(P117L) and PS1V97L Tg mice showed

accumulation of Aβ oligomer (AβO) (Wang et al., 2016;

Zhang et al., 2014;Zufferey et al., 2013). Increased tau

phosphorylation was detected in PS1(P117L), PS1(I213T)

2Li, X., et al. Sci China Life Sci

Table 1 Characteristics of PSEN1 single mutation mouse modelsa)

Mutation

site Model name Aβ Tau Neuronal damage Gliosis Synaptic changes Changes in LTP/

LTD Cognitive dysfunc-

tion References

PSEN1

A246E PS1(A246E) Absent up to 24 months. Absent up to

24 months. ———

A weak stimulation

at Schaeffer’s

collaterals to CA1

neuron synapses

elicited LTP.

Absent at 1 and

9 months. (Schneider et al.,

2001)

PSEN1

I213T PS1(I213T)

KI Elevated Aβ42(43) at

4–5 months.

Tau phosphorylation

in hippocampal neu-

rons at 7 months and

in CA3 neurons at

15 months

β-sheet structure of

tau fibrils and

tangles at 16 months.

————Spatial learning

deficits at

11 months.

(Lalonde and Stra-

zielle, 2005;Naka-

no et al., 1999;

Tanemura et al.,

2006)

PSEN1

M146L

(A>C) PS1(M146L) Elevated Aβ42(43). Absent. — Absent. —

Larger medium and

late after hyperpo-

larizations in CA3

pyramidal cells at

1–2 months.

Absent in Y maze

at 3–3.5 months.

(Barrow et al.,

2000;Begley et al.,

1999;Duff et al.,

1996;Holcomb et

al., 1998)

PSEN1

M146V

PS1(M146V) Selective increase

in Aβ42(43). Absent. — Absent. —

Larger medium and

late after hyperpo-

larizations in CA3

pyramidal cells at

1–2 months.

—

(Barrow et al.,

2000;Begley et al.,

1999;Duff et al.,

1996)

PS1(M146V)

KI Absent. Absent. Reduced adult

neurogenesis in DG

at 3 months. Absent. Absent. Absent at

3 months.

Impaired contex-

tual fear learning at

3 months.

(Guo et al., 1999;

Wang et al., 2004)

PSEN1

P117L PS1(P117L)

(line 13)

Increased Aβ42 at 2 months;

increased AβOs in CA1

and amygdala at 10

months.

Tau phosphorylation

at 10 months

Impaired neurogen-

esis at 1 month;

impaired neural

progenitor cells

survival.

————

(Wen et al., 2004;

Wen et al., 2002;

Zufferey et al.,

2013)

PSEN1

V97L PS1V97L Tg

Increased Aβ42 and Aβ42/

Aβ40 ratio at 9 months;

intraneuronal AβO

accumulation in cortex at

6 months and in

hippocampus at 9 months;

absent of plaques up to

24 months.

Tau phosphorylation

at 9 months; tangles

formed at 12 months.

Neuronal damage

occasionally at

10-14 months;

neuronal degenera-

tion at 24 months.

Microglia activa-

tion in cortex and

astrocyte activation

at 6 months;

microglia activa-

tion in hippocam-

pus at 9 months.

Synaptophysin re-

duction in

hippocampus at

9 months;

decreased synaptic

density at

12 months.

Decreased LTP

in hippocampus

at 6 months.

Spatial learning

and memory defi-

cits at 9 months.

(Wang et al., 2016;

Wang et al., 2012;

Zhang et al., 2014)

a) The table is ordered by mutation site alphabetically. “—” means no data.

Li, X., et al. Sci China Life Sci

KI and PS1V97L Tg mice, but neurofibrillary tangles (NFTs)

could be observed only in PS1V97L Tg mice (Tanemura et

al., 2006;Wang et al., 2012;Zufferey et al., 2013). PS1

(M146V) KI and PS1(P117L) mice showed impaired neu-

rogenesis at young age (Guo et al., 1999;Wen et al., 2004).

PS1(M146V) KI, PS1V97L Tg and PS1(I213T) KI mice

showed cognitive impairment at 3, 9 and 11 months of age,

respectively (Lalonde and Strazielle, 2005;Wang et al.,

2004;Zhang et al., 2014). None of the PSENs transgenic

models showed gliosis, synaptic changes, or neuronal de-

generation except PS1V97L Tg mice (Wang et al., 2012).

None of the PSENs transgenic models showed neuronal

death. Major PSEN1 models with more than three patholo-

gical or cognitive changes are described below.

PS1(I213T) KI mice

PS1(I213T) KI mice were constructed using embryonic stem

cell gene targeting technology and introducing I213T mis-

sense mutation into exon 7 of mouse PSEN1 gene (Nakano et

al., 1999). The mice showed elevated Aβ42 and Aβ42/40

ratio in brain at 4–5 months (Nakano et al., 1999), by im-

pairing catalytic activity of γ-secretase-mediated γ-site

cleavage (Shimojo et al., 2008). Tau phosphorylation were

detected in hippocampal neurons at 7 and 15 months, and β-

sheet structure of tau fibrils and tangles appeared at

16 months (Tanemura et al., 2006). Spatial learning deficits

were detected by Morris water maze (MWM) at 11 months

(Lalonde and Strazielle, 2005).

PS1(P117L) mice

PS1(P117L) mice were constructed using random transgenic

technology and overexpressing the P117L mutation of hu-

man PSEN1 driven by neuron specific enolase promoter

(Wen et al., 2002). The mice showed impaired neurogenesis

as early as 1 month (Wen et al., 2004), plaque and tau

phosphorylation in CA1 region at 10 months (Zufferey et al.,

2013). This mouse model was crossed with APP KI mice to

study the synergistic effect of the pathogenic mutations in

APP and PS1 genes in AD, such as AppNL-FPsen1P117L dou-

ble-mutant mice (Sato et al., 2021).

PS1V97L Tg mice

PS1V97LTg mice were constructed using random transgenic

technology and overexpressing human PSEN1 gene with

V97L mutation (from Chinese FAD) driven by the platelet-

derived growth factor (PDGF)-β promoter (Wang et al.,

2012). The earliest pathologies in PS1V97L Tg mice were

Aβ accumulation, glial cell activation and decreased hippo-

campal long-term potentiation (LTP) at the age of 6 months

(Zhang et al., 2014). Intraneuronal AβOs appeared first in the

cortex at 6 months, and progressed to hippocampus at

9 months (Zhang et al., 2014). Microglia activation appeared

in the cortex at 6 months and hippocampus at 9 months

(Zhang et al., 2014). Astrocyte activation in the cortex and

hippocampus started at 6 months, and accumulated over time

(Zhang et al., 2014). Spatial learning and memory decline

started at 9 months (Wang et al., 2012). At the same time, tau

phosphorylations at Ser199, Ser202, Thr231, Ser396, and

Ser404 were significantly increased in CA3/CA4 regions of

hippocampus (Wang et al., 2012). Age-related synaptophy-

sin decreased in hippocampus at 9 months, especially in the

CA3 region (Zhang et al., 2014). Tangle-like structures and

atrophic degenerated neurons appeared in the frontal cortex

at 10 months (Wang et al., 2012). Synaptic density decreased

significantly at 12 months. Neuronal damage could be seen

occasionally at 10 and 14 months, accompanied by en-

largement of lateral ventricle. Neuronal degeneration oc-

cured at 24 months, but there were no neuronal loss or

plaques even at 24 months (Zhang et al., 2014). PS1V97L Tg

mice also exhibited enhanced neuroinflammation and oxi-

dative stress (Hou et al., 2018;Wang et al., 2016), abnorm-

alities of mitochondrial membrane potential via the Sirtuin 3

(SIRT3) pathway (Li et al., 2018), and decreased Nrf2/ARE

signaling pathway activity (Tian et al., 2019). Using this

model, sulforaphane and honokiol were found to alleviate

cognitive impairment caused by AβOs (Hou et al., 2018;Li

et al., 2018;Tian et al., 2019). Figure 1 summarized the

timeline and major pathological changes of PS1V97L Tg

mice.

APP single-transgenic mouse models

APP encodes amyloid precursor protein, a transmembrane

protein which is cleaved to form amyloidogenic Aβ peptides.

73 mutations in APP have been reported, and are associated

with familial forms of early onset AD as well as with cerebral

amyloid angiopathy (CAA). Thirteen mouse models carrying

single mutation of APP with more than one pathological

change or cognitive impairment are shown in Table 2

(Boncristiano et al., 2005;Brown et al., 2005;Calhoun et al.,

1998;Chapman et al., 1999;Dodart et al., 1999;Domnitz et

al., 2005;Frautschy et al., 1998;Games et al., 1995;Herzig

et al., 2004;Hsiao et al., 1996;Hwang et al., 2004;Irizarry et

al., 1997;Jacobsen et al., 2006;Kawasumi et al., 2004;Kelly

et al., 2003;Kim et al., 2012;Kulnane and Lamb, 2001;Lanz

et al., 2003;Larson et al., 1999;Lehman et al., 2003;Lord et

al., 2006;Lord et al., 2011;Marazuela et al., 2022;Masliah

et al., 2001;Moechars et al., 1999;Philipson et al., 2009;

Puig et al., 2004;Reichwald et al., 2009;Richards et al.,

2003;Richardson et al., 2003;Roder et al., 2003;Rönnbäck

et al., 2012;Snellman et al., 2013;Stalder et al., 1999;

Sturchler-Pierrat et al., 1997;Tomiyama et al., 2010;To-

miyama et al., 2008;Van Dam et al., 2003;Van Dorpe et al.,

4Li, X., et al. Sci China Life Sci

2000). Plaques appeared in the human APP Swedish muta-

tion (KM670/671NL), Indiana mutation (V717F), and Lon-

don mutation (V717I) mice, but not in APPSw-NSE mice

(Games et al., 1995;Hsiao et al., 1996;Lehman et al., 2003;

Lord et al., 2011;Moechars et al., 1999;Richards et al.,

2003;Richardson et al., 2003;Sturchler-Pierrat et al., 1997).

NFTs were absent in all APP single mutant mice. Only APP

E693Δ-Tg and APP23 mice showed significant hippocampal

neuron death (Calhoun et al., 1998;Tomiyama et al., 2010).

APP23 and PDAPP mice showed the earliest cognitive im-

pairment, at 3 months of age (Dodart et al., 1999;Van Dam et

al., 2003), while other models including APP E693Δ-Tg,

APPSw-NSE, Tg2576, TAS10 and APP (V717I) mice

showed spatial memory deficits at 6–12 months (Hsiao et al.,

1996;Hwang et al., 2004;Moechars et al., 1999;Richardson

et al., 2003;Tomiyama et al., 2010). Different from other

APP models, APP(V642) KI mouse model was generated

using targeted knock-in of the V642I (corresponds to human

APP V717I) mutation into the exon 17 of mouse APP gene,

which showed cognitive impairment at 26–27 months (Ka-

wasumi et al., 2004). Major APP models with more than

three pathological or cognitive changes are described below.

APPE693Δ-Tg mice

This model expresses low levels of human APP (isoform

695) carrying the E693Δ(Osaka) mutation under the control

of the mouse prion promoter (Tomiyama et al., 2010). The

expression levels of human APP in the mice were similar to

those of endogenous mouse APP (Tomiyama et al., 2010).

Figure 1 The timeline and major pathological changes of the PS1V97L Tg mice. PS1V97L mutation was found in 2003, and PS1V97L Tg mouse model

was established in 2012–2014. Series of neuropathological and behavioral changes as well as underlying mechanisms were discovered subsequently,

including increased intraneuronal AβOs, microglial activation, impairment of LTP, increased phosphorylation of tau, increased levels of various inflammatory

factors, cognitive impairment in the MWM, NFT-like structures, and reduced synaptic density. No significant amyloid plaque or neuronal loss was found.

Li, X., et al. Sci China Life Sci

Table 2 Characteristics of APP single mutation mouse modelsa)

Mutation site Model name Aβ Tau Neuronal damage Gliosis Synaptic

changes Changes in

LTP/LTD Cognitive

dysfunction References

APP E693del

(Osaka) APP E693Δ-Tg

(Osaka)

AβO accumulation within

neurons at 8 months; no

plaques.

No tangles;

abnormal tau

phosphorylation

at 8 months.

Neuronal loss in

hippocampal CA3

region at

24 months.

Microgliosis at 12 months;

astrocytosis at 18 months.

Decrease in

synaptic den-

sity in hippo-

campal CA3

region at

8 months.

Reduced short

term plasticity

and LTP at

8 months.

Memory

impairment in

MWM

at 8 months.

(Tomiyama et al.,

2010;Tomiyama et

al., 2008)

APP E693G

(Arctic) TgAPParc

Diffused extracellular Aβ

deposition in subiculum

at 7–9 months; in inter-

connected regions at

12–15 months.

— — — — — — (Rönnbäck et al.,

2012)

APP E693Q

(Dutch) APPDutch

No plaques; increased

Aβ40/Aβ42 ratio; Aβ de-

position in blood vessel at

22–24 months.

Absent. —

Microgliosis adjacent to

amyloid-laden vessels and

astrocyte activation in CAA

affected neocortical regions

earlier than 29 months.

— — — (Herzig et al.,

2004)

APP

KM670/

671NL

(Swedish)

APP23

Aβ plaques at 6 months,

faster in female; Aβ de-

position in neocortex at

12 months;

age-related increase in

vascular Aβ deposits by

12 months; plaques occu-

py more than 25% of

neocortex and hippocam-

pus by 24 months.

No tangles;

hyperphosphorylated

tau in dystrophic

neurites around Aβ

plaques at 6 months.

14%–28%

neuronal loss in

hippocampal CA1

region at

14–18 months.

Microglia activation at

4–9 months; increased C1q

at 9 months; increased C3 at

18 months; upregulation of

neuro-inflammation mar-

kers, activated astrocytes

and macrophage at

20 months.

Absent at

24 months.

Absent at 3, 6,

9, 12, 18, or

24 months.

Spatial memory

deficit in MWM

at 3 months.

(Boncristiano et al.,

2005;Calhoun et

al., 1998;Kelly et

al., 2003;Marazue-

la et al., 2022;

Reichwald et al.,

2009;Roder et al.,

2003;Snellman et

al., 2013;Stalder et

al., 1999;Sturchler-

Pierrat et al., 1997;

Van Dam et al.,

2003)

APPSwe

Aβ plaques in neocortex

and hippocampus at

17–18 months; Aβ40 5–

10 times higher than

Aβ42.

— — — — — — (Richards et al.,

2003)

APP(Swedish)

(R1.40)

Aβ deposition in frontal

cortex at 14–16 months;

spread to whole cortex at

18–20 months; occasional

deposit in corpus callo-

sum and hippocampus.

No tangles;

phosphorylated

tau at

14–16 months.

—Plaque-related reactive

astrocyte and microglia

at 14–16 months. — Absent. — (Kulnane and

Lamb, 2001;Leh-

man et al., 2003)

APPSw-NSE Increased Aβ42 in cortex

and hippocampus at

12 months; no plaques.

Increased tau

phosphorylation at

12 months.

Increased caspase-3

staining neuron and

TdT-mediated

dUTP Nick-End

Labeling (TU-

NEL)-stained nu-

clei in cortex and

hippocampus at

12 months.

— — — Longer escape

latency in MWM

at 12 months.

(Hwang et al.,

2004;Kim et al.,

2012)

(To be continued on the next page)

6Li, X., et al. Sci China Life Sci

(Continued)

Mutation site Model name Aβ Tau Neuronal damage Gliosis Synaptic

changes Changes in

LTP/LTD Cognitive

dysfunction References

TAS10

(thy1-APPswe)

Aβ40 and Aβ42 accumu-

lation and fibrillar amy-

loid plaques in cortex and

hippocampus

at 12 months; increase

progressively up to

24 months.

Absent. — Astrocytes and microglia

proliferation in DG at

6 months.

Dystrophic

synapses at

6 months;

decreased

synapse num-

ber at

24 months.

—

Spatial memory

deficits in MWM

at 6 months;

defects of

spontaneous

alternating

behavior in Y

maze at

12 months.

(Brown et al.,

2005;Richardson

et al., 2003)

tg-APPSwe

Intraneuronal Aβ aggre-

gation at 6 months; CAA

and congophilic parench-

ymal plaques in cortex,

hippocampus and

thalamus at 9 months;

extracellular amyloid

deposition and plaques

formation at 12 months.

Absent. Absent.

Microgliosis and astroglio-

sis in hippocampus, thala-

mus, and around plaques in

cortex at 12 months.

— — —

(Lord et al., 2006;

Lord et al., 2011;

Philipson et al.,

2009)

Tg2576

Aβ plaques and vascular

Aβ deposition at

11–13 months; extensive

CAA at 22 months.

Hyperphosphorylated

tau in neurites around

plaques at 16 months.

Absent or very

limited.

Increase in microglial

density and size at

10–16 months.

Dendritic spine

loss by

4.5 months in

hippocampal

CA1 region.

Decline in

LTP in DG at

5 months.

Impaired spatial

learning, working

memory, and

contextual fear

conditioning at

9 months.

(Chapman et al.,

1999;Domnitz et

al., 2005;Frautschy

et al., 1998;Hsiao

et al., 1996;Irizarry

et al., 1997;Jacob-

sen et al., 2006;

Lanz et al., 2003;

Puig et al., 2004)

APP V717F

(Indiana) PDAPP (line109)

No plaques at

4–6 months; Aβ deposi-

tion at 6 months; detect-

able CAA at 24 months.

No tangles;

phosphorylated tau in

dystrophic neurites

after 14 months.

Absent. Microglia and astrocytes

activation at 6–9 months.

Decreased sy-

naptic density

in DG at

8 months.

Alterations in

theta burst

stimulation

induced LTP

at 4–5 months.

Robust deficits

in RAM at

3 months.

(Dodart et al.,

1999;Domnitz et

al., 2005;Games et

al., 1995;Larson et

al., 1999;Masliah

et al., 2001)

APP V717I

(London)

APP (V717I)

Plaques in cortex and

subiculum at 10 months;

diffuse amyloid deposi-

tion and dense neuritis

plaques at 13–18 months;

amyloid deposition in

cerebral vessels and de-

creased Aβ42/40 ratio at

15 months.

No tangles;

hyperphosphorylated

tau at 16 months. Absent.

Microglia activation and

other neuro-inflammatory

markers increase at

10 months.

—

LTP deficit in

hippocampal

CA1 region

at 6 months.

Spatial and

non-spatial

orientation,

memory

impairment in

MWM and

associative

learning deficits

at 6 months.

(Moechars et al.,

1999;Van Dorpe et

al., 2000)

APP (V642I)KI Increased Aβ42(43)/40

ratio at 29 months. Absent. Absent. — — — Long-term

memory deficit

at 27–29 months.

(Kawasumi et al.,

2004)

a) The table is ordered by mutation site alphabetically. “—” means no data.

Li, X., et al. Sci China Life Sci

Accumulating AβO within neurons of the hippocampus and

cortex were found at 8 months of age, but no amyloid pla-

ques even at 24 months of age (Tomiyama et al., 2010). The

mice exhibited hyperphosphorylated tau, decreased synaptic

density in the hippocampal CA3 region and memory im-

pairment at 8 months of age, microgliosis in the hippo-

campus and cortex at 12 months, astrocytosis at around

18 months, and neuronal loss in the CA3 region at 24 months

(Tomiyama et al., 2010). This mouse model was crossed with

other transgenic mice to study the combined role of two

genes in AD, such as tau264 mice (Umeda et al., 2014).

APP23 mice

This transgenic mouse model expresses human APP (iso-

form 751) containing the KM670/671NL (Swedish) muta-

tion under the murine Thy1 promoter, and has a 7-fold

overexpression of mutant human APP (Sturchler-Pierrat et

al., 1997). The mice first developed cognitive impairment at

3 months of age (Van Dam et al., 2003). Aβ deposits were

first observed at 6 months of age, visualized in neocortex by

pittsburgh compound B (PiB) positron emission tomography

(PET) at 12 months (Snellman et al., 2013). The mice also

showed age-associated increase in components of the com-

plement system, namely C1q and C3, at 9 months (Reich-

wald et al., 2009). Dense-core amyloid plaques were formed

at 6 months which increased with age and faster in female

mice, and occupied more than 25% of neocortex and hip-

pocampus at 24 months of age (Calhoun et al., 1998;

Sturchler-Pierrat et al., 1997). Plaques were surrounded by

activated microglia, astrocytes, and dystrophic neurites with

hyperphosphorylated tau, but NFTs were not found (Stalder

et al., 1999;Sturchler-Pierrat et al., 1997). The number of

hippocampal neurons decreased by 14%–28% at

14–18 months (Calhoun et al., 1998). This mouse model was

used to study the treatment of AD with anti-Aβ antibodies

and other drugs that block the formation of Aβ multimers

(Leinenga et al., 2021;Wilhelmus et al., 2022).

TAS10 (Thy1-APPswe) mice

This transgenic mouse overexpresses human APP (isoform

695) with the KM670/671NL (Swedish) mutation driven by

the murine Thy-1 promoter (Richardson et al., 2003). These

mice accumulated Aβ40 and Aβ42 in the cortex and hippo-

campus, and developed amyloid plaques by 12 months, with

higher overall levels in the cortex by 18 months (Richardson

et al., 2003). Cognitive impairment appeared in MWM at

6 months, and in Y maze at 12 months. The mice also ex-

hibited dystrophic neurites, lipid deposits, astrogliosis and

microgliosis in the dentate gyrus (DG) at 6 months. The mice

had more synapses than non-Tg mice before 12 and

18 months of age, but had fewer synapses by 24 months of

age (Richardson et al., 2003).

Tg2576 mice

This transgenic mouse model overexpresses human APP

(isoform 695) with the KM670/671NL (Swedish) mutation

driven by the hamster prion protein promoter (Hsiao et al.,

1996). The mice first showed synaptic morphological and

functional changes such as dendritic spine loss in CA1 region

and severely impaired LTP in CA1 and DG of the hippo-

campus at 4–5 months (Chapman et al., 1999;Lanz et al.,

2003), and impaired spatial learning, working memory and

contextual fear conditioning after 9 months of age (Hsiao et

al., 1996;Irizarry et al., 1997). Hemizygous mice developed

many Aβ plaques along with some vascular amyloid by

11–13 months (Irizarry et al., 1997), and significantly in-

creased microglial density and size in plaque-forming areas

of hippocampus, frontal, entorhinal and occipital cortex at 10

and 16 months (Frautschy et al., 1998). There was hyper-

phosphorylated tau in neurites around plaques at 16 months,

but no tangles or neuron loss (Irizarry et al., 1997;Puig et al.,

2004). These mice developed extensive CAA at 22 months

(Domnitz et al., 2005). This mouse model was widely used in

researches of pathogenesis and therapeutics of AD, and was

often used in constructing new AD models, such as 5×FAD

(Oakley et al., 2006). Aducanumab, bexarotene, memantine,

and high-fat diet treatment were studied using this mouse

model and showed beneficial effects on cognitive behaviors

(Cramer et al., 2012;Elhaik Goldman et al., 2018;Nagakura

et al., 2013;Sevigny et al., 2016). Oat extract avenan-

thramide-C prevented the impairment of hippocampal sy-

naptic plasticity in this model (Lee et al., 2021b).

PDAPP (line109) mice

This model has a PDGF-driven human APP minigene with

the V717F (Indiana) mutation, and overexpresses human

APP more than 10-fold higher than endogenous murine APP

(Games et al., 1995). The mice showed cognitive deficits in a

bar press learning task and radial arm maze (RAM) at

3 months, in spatial working memory in MWM at 4 months,

in recognition memory in novel object recognition (NOR)

task at 6 months, and worsened with age (Dodart et al., 1999;

Hartman et al., 2005). The mice showed changes in synaptic

transmission and plasticity including enhanced paired-pulse

facilitation, distorted responses to high frequency stimula-

tion bursts, and more rapidly decayed LTP at 4–5 months,

and decreased synaptic and dendrite density at 8 months

(Larson et al., 1999). Aβ deposition occurred in the hippo-

campus, corpus callosum and cerebral cortex at 6–9 months,

and plaques deformed extensively with age. Astrocytes and

activated microglia were associated with plaques. Tau

phosphorylation was observed in dystrophic neurites at

8Li, X., et al. Sci China Life Sci

16 months of age (Dodart et al., 1999;Games et al., 1995).

CAA was detectable at 24 months (Domnitz et al., 2005).

This mouse model was often used in the researches of pa-

thogenesis and therapeutics of AD. In this model, 2B3 (an

antibody that recognizes the β-secretase cleavage site on

APP but not Aβ) was reported to selectively affect APP

metabolism by reducing beta-site APP-cleaving enzyme 1

(BACE1) activity and reverse an age-dependent associative

recognition memory deficit (Evans et al., 2019), and sema-

gacestat (a γ-secretase inhibitor) showed sustained and dose-

dependent inhibition of Aβ production in plasma and cere-

brospinal fluid (CSF) (Karran and Hardy, 2014).

APP(V717I) mice

This model overexpresses human APP (isoform 695) with

the V717I (London) mutation driven by the Thy1 promoter

(Moechars et al., 1999). The earliest pathological manifes-

tations included reduced LTP, impairments in spatial and

non-spatial orientation, and deficits in memory in MWM and

associative learning at 6 months of age. Plaques began to

develop in the cortex and subiculum at 10 months. Diffused

amyloid deposits and compact neuritic plaques were ob-

served at 13–18 months, especially in the hippocampus and

cortex, with occasional deposits in the thalamus and fimbria,

external capsule, pontine nuclei, and white matter (Moechars

et al., 1999). Prominent amyloid deposits were observed in

brain vessels and microbleeds at 15 and 25–30 months of

age, respectively (Van Dorpe et al., 2000). The mice ex-

hibited microglia activation and increased neuro-in-

flammatory markers at 10 months, tau hyperphosphorylation

in dystrophic neurites at 16 months, but was absent of tan-

gles. This mouse model was used to generate mouse model to

study the combined role of two genes in AD, including APP

(V717I)×PS1(A246E) mice (Dewachter et al., 2000).

MAPT single-transgenic mouse models

MAPT encodes the microtubule associated protein tau, a

protein central to AD neuropathology. Human tau protein has

six isoforms, that differ in the number of amino-terminal

repeats (0N, 1N or 2N) and microtubule-binding repeats (3R

or 4R) (Götz et al., 2018). The transformation from 3R to 4R

is the basis for the development of NFTs (Hara et al., 2013).

However, there is only 4R isoform in mice, which cannot

naturally develop tangles with age, so MAPT transgenic mice

were established as tau pathological models for AD research

(Watamura et al., 2022a). MAPT mutations are commonly

found in frontotemporal dementia, and the A152T, K280Δ

and R406W mutations have been reported in sporadic AD

(Coppola et al., 2012). MAPT single mutation mouse models

are lack of Aβ pathology. Eleven mouse models carrying a

single mutation of MAPT with more than one pathological

change or cognitive impairments are shown in Table 3

(Bellucci et al., 2004;Boekhoorn et al., 2006;Cook et al.,

2014;Decker et al., 2016;Decker et al., 2015;Dennissen et

al., 2016;Eckermann et al., 2007;Gelman et al., 2018;

Hampton et al., 2010;Helboe et al., 2017;Hoover et al.,

2010;Kopeikina et al., 2013;Lasagna-Reeves et al., 2016;

Lewis et al., 2000;Maeda et al., 2016;Maurin et al., 2014;

Mocanu et al., 2008;Ramsden et al., 2005;SantaCruz et al.,

2005;Scattoni et al., 2010;Spires et al., 2006;Sydow et al.,

2016;Sydow et al., 2011;Takeuchi et al., 2011;Tanemura et

al., 2001;Tanemura et al., 2002;Tatebayashi et al., 2002;

Terwel et al., 2005;Van der Jeugd et al., 2012;Xu et al.,

2014;Yoshiyama et al., 2007;Yue et al., 2011). All MAPT

single mutant mice showed tau hyperphosphorylation, and

tangles were seen in most mice except hTau-AT or Tau

R406W Tg mice (Decker et al., 2016;Eckermann et al.,

2007;Lewis et al., 2000;Maeda et al., 2016;Mocanu et al.,

2008;Ramsden et al., 2005;Sydow et al., 2016;Tanemura et

al., 2001;Tatebayashi et al., 2002;Terwel et al., 2005;Xu et

al., 2014;Yoshiyama et al., 2007). Significantly neuronal

loss, gliosis, synaptic changes and cognitive dysfunction

were observed in hTau-AT, TauRDΔK280, JNPL3(P301L),

rTg4510, hTau.P301S and Tau P301S (PS19) mice (Bellucci

et al., 2004;Cook et al., 2014;Hampton et al., 2010;Helboe

et al., 2017;Kopeikina et al., 2013;Lewis et al., 2000;Maeda

et al., 2016;Mocanu et al., 2008;Ramsden et al., 2005;

SantaCruz et al., 2005;Scattoni et al., 2010;Spires et al.,

2006;Sydow et al., 2016;Sydow et al., 2011;Xu et al., 2014;

Yue et al., 2011). The MAPT mouse models commonly used

in AD studies are described below.

JNPL3(P301L) mice

JNPL3 mice were constructed using random transgenic

technology and overexpressing human tau (4R0N) with the

P301L mutation driven by the mouse prion promoter

(MoPrP) (Lewis et al., 2000). Homozygous JNPL3 mice

expressed human tau at about twice the endogenous level and

were most strongly expressed in the cerebellum and hippo-

campus (Lewis et al., 2000). NFTs appeared at 4.5 months in

homozygotes and 6.5 months in heterozygotes. NFTs were

morphologically heterogeneous, including flame- or glo-

bose-shaped NFT, Pick bodies and smaller, more irregular,

dense cytoplasmic inclusions (Lewis et al., 2000). Neuronal

loss, especially in the spinal cord, and astrogliosis near NFTs

were observed at 10 months (Lewis et al., 2000). 90% JNPL3

mice exhibited motor and behavioral problems by 10 months

(Lewis et al., 2000). This model is often used to evaluate the

effect of different types of tau antibodies on tau pathology of

AD, such as single domain antibodies (Congdon et al., 2022),

phosphorylated tau-specific intrabodies (Goodwin et al.,

2021), vectorized single chain variable fragment (Vitale et

al., 2020), and the interaction between Aβ and tau by

Li, X., et al. Sci China Life Sci

Table 3 Characteristics of MAPT single mutation mouse modelsa)

Mutation site Model name Aβ Tau Neuronal damage Gliosis Synaptic changes Changes in LTP/

LTD Cognitive dysfunc-

tion References

MAPT A152T

hTau-AT

(hTau40-AT) —

Hyperphosphorylated tau

and tangles in

hippocampus, cortex,

cerebellum and spinal

cord at 3 months.

Neuronal loss in

hippocampus and

cortex at

12 months.

Astrocytosis and

microgliosis at

10 months.

Decreased synaptophysin

in hippocampus and cor-

tex at 12 months; in-

creased spines in CA3 at

12 months; decreased in

CA1 and CA3 at

16 months.

Absent at

20 months.

Learning and

memory deficits in

MWM at 16 months.

(Decker et al.,

2016;Sydow et al.,

2016)

hTau-A152T —

No tangles; abnormal

accumulations and

phosphorylation of

soluble tau in neurons

at 8 months.

Neuron loss in

hippocampus at

20 months.

Astrocytosis at

6 months. —No changes at

20 months.

Impaired nest

building at

10–14 months;

learning and

memory deficits

at 17 months.

(Maeda et al.,

2016)

MAPT

K280del

TauΔK280

(“Proaggregation

mutant”) Absent.

Widespread pre-tangle tau

pathology and

hyper-phosphorylation;

tangles after 24 months.

Absent. —

Synaptic loss in

hippocampus at

13 months; pre- and

post-synaptic protein

reduction; decreased

number of dendrite

and spine.

LTP reduction

from DG to CA3

in hippocampus

at 12 months.

Cognitive deficit

at 16 months.

(Dennissen et al.,

2016;Eckermann

et al., 2007;Van

der Jeugd et al.,

2012)

TauRDΔK280

(“Proaggregation

mutant”) Absent.

Tangles at 2–3 months;

from entorhinal to

neocortex by

15 months.

Neuronal loss in

hippocampus at

5 months.

Astrocytosis in

hippocampus,

entorhinal and

piriform cortex

at 21 months.

Structural changes of

synapse in mossy fiber

and CA3; synaptic loss

in hippocampus after

9.5 months.

LTP and

long-term

depression

(LTD) deficits

after 10 months.

Learning and

memory deficits in

MWM and passive

avoidance test after

10 months.

(Decker et al.,

2015;Mocanu et

al., 2008;Sydow et

al., 2011)

MAPT P301L

JNPL3(P301L) Absent. NFTs at 4.5 months. Motor neuron loss,

especially in

spinal cord.

Astrogliosis in

brainstem,

diencephalon, and

basal telencephalon

by 10 months.

— —

Motor impairment

and behavioral

problems at

10 months.

(Lewis et al., 2000)

rTg(tauP301L)

4510 Absent.

Pre-tangles at 2.5 months;

argyrophilic tangle-like

inclusions in cortex at

4 months and in

hippocampus at 5.5 months.

Decreased

hippocampal CA1

neurons by

5.5 months; cortical

cell loss at

8.5 months;

forebrain

atrophy at

10 months.

Microgliosis and

astrocytosis at

2.5 months.

Decreased pre- and

postsynaptic proteins

at 6–12 months;

dendritic spine loss

at 8–9 months.

Impaired LTP

at 4.5 months.

Spatial navigation

deficits in MWM

at 1.3 months;

spatial memory

deficits at

2.5–4 months;

fear conditioning

deficits at

2–6 months.

(Cook et al., 2014;

Gelman et al.,

2018;Helboe et al.,

2017;Hoover et al.,

2010;Kopeikina et

al., 2013;Ramsden

et al., 2005;Santa-

Cruz et al., 2005;

Spires et al., 2006;

Yue et al., 2011)

Tau P301L Absent.

Tau hyperphosphorylation

and conformational changes

at 7 months; tangle-like

pathology by 8 months;

age-dependent increase

in total tau.

—Astrogliosis by

7 months. —

LTP deficit in

hippocampal

CA1 region at

6 months.

Deficits in passive

avoidance task at

5 months; in NOR

task at 9 months;

motor impairment

at 7 months.

(Boekhoorn et al.,

2006;Maurin et al.,

2014;Terwel et al.,

2005)

(To be continued on the next page)

10 Li, X., et al. Sci China Life Sci

(Continued)

Mutation site Model name Aβ Tau Neuronal damage Gliosis Synaptic changes Changes in LTP/

LTD Cognitive dysfunc-

tion References

MAPT P301S

hTau.P301S Absent. NFTs at 4 months. Neuronal loss at

3 months.

Microglial

activation in brain

stem and spinal

cord at 5 months;

astrocytosis at

6 months.

Decreased spine density

and length in

hippocampus at

2.5 months.

—Memory deficit in

MWM at

2.5 months.

(Bellucci et al.,

2004;Hampton et

al., 2010;Scattoni

et al., 2010;Xu et

al., 2014)

Tau P301S

(Line PS19) Absent.

Tangles in neocortex,

amygdala, hippocampus,

brain stem and spinal cord

at 6 months.

Neuron loss in

hippocampus at

8 months, and in

entorhinal cortex,

piriform cortex

and amygdala at

12 months.

Microgliosis at

3 months, espe-

cially in white

matter and spinal

cord;

increased

microgliosis by

6 months in

hippocampus,

amygdala,

entorhinal cortex

and spinal cord.

Decreased synaptophysin

in hippocampal CA3

region at 3–6 months.

Reduced LTP

in CA1 region

of hippocampus

at 6 months.

Impaired spatial

learning and memory

in MWM at

6 months; impaired

memory

in contextual fear

conditioning test at

7.5 months.

(Lasagna-Reeves et

al., 2016;Takeuchi

et al., 2011;

Yoshiyama et al.,

2007)

MAPT R406W Tau R406W

transgenic Absent.

Tau inclusions (mainly

filaments) in neurons of

forebrain, hippocampus

and amygdala at

18 months.

— — — —

Impairmed contextual

and cued fear

conditioning at

16–23 months.

(Tatebayashi et al.,

2002)

MAPT V337M

(Seattle) Tau V337M Absent.

Phosphorylated and

ubiquitinated tau

aggregates in

hippocampus at

11 months; tangles

formation in

hippocampus between

4–11 months.

Irregularly shaped

neurons and

non-apoptotic

atrophic

degeneration in

hippocampus at

10 months;

decreased

hippocampal neural

activity at

15 months.

— — — No differences in

MWM at

11 months.

(Tanemura et al.,

2001;Tanemura et

al., 2002)

a) The table is ordered by mutation site alphabetically. “—” means no data.

Li, X., et al. Sci China Life Sci

hybridizing with Tg2576 or 5×FAD mice models (Kang et

al., 2021;Kwan et al., 2022).

rTg(tauP301L)4510 mice

rTg(tauP301L)4510 mice express human tau (4R0N) with

the P301L mutation driven by a tetracycline operator up-

stream of a cytomegalovirus minimal promoter and a tetra-

cycline-controlled transactivator driven by forebrain-specific

Ca2+ calmodulin kinase II promoter system, which restricts

transgene expression to the forebrain and can be inhibited by

doxycycline (Ramsden et al., 2005). The expression of mu-

tant tau protein in rTg(tauP301L)4510 mice was about 13

times higher than that of endogenous tau protein, with the

highest in the hippocampus and cortex (Ramsden et al.,

2005). The model mice showed a series of behavioral

changes, such as spatial navigation deficits at 1.3 months,

impaired spatial reference memory at 2.5 months (Ramsden

et al., 2005), deficits in fear conditioning between 2 months

and 6 months (Cook et al., 2014), anxiety at 6 months and

motor dysfunction at 10 months (Cook et al., 2014;Ramsden

et al., 2005). The mice exhibited gliosis, pathological tau

conformation and phosphorylation in the hippocampus and

neocortex at 2.5 months, developed NTFs in the cortex at

4 months and hippocampus at 5.5 months (Helboe et al.,

2017;Ramsden et al., 2005). Neuronal loss first occurred in

DG region at 2.5 months, followed by CA1 and CA2/3 at

5.5 months, and later in cortex at 8.5 months (Spires et al.,

2006). Impaired LTP in the CA1 hippocampal region were

observed at 4.5 months (Hoover et al., 2010). Decreased pre-

and post-synaptic proteins began between 6 and 12 months,

decreased dendritic spine density occurred at 8.5 months

(Kopeikina et al., 2013). Brain weight decreased at 7 months

and forebrain atrophy was observed at 10 months (SantaCruz

et al., 2005). Doxycycline can suppress tau P301L expres-

sion at different time points, and delay tau pathology,

maintain the number of neurons and brain weight, and im-

prove spatial memory (Helboe et al., 2017;SantaCruz et al.,

2005). This model has also been used to evaluate the treat-

ment effects of trazodone, epicatechin, LDN/OSU-0215111

(a novel excitatory amino acid transporter 2 translational

activator) on tau pathology and cognitive deficits (de Oli-

veira et al., 2022;Foster et al., 2019;Hole et al., 2021).

Tau P301S (Line PS19) mice

Tau P301S (Line PS19) mice were constructed using random

transgenic technology and overexpressing human tau

(4R1N) with the P301S mutation driven by the MoPrP

(Yoshiyama et al., 2007). The expression of mutant tau

protein in Tau P301S (Line PS19) mice was about 5 times

higher than that of endogenous tau protein (Yoshiyama et al.,

2007). This model showed tau hyperphosphorylation, im-

paired axonal transport, microgliosis, decreased synapto-

physin, and motor deficits as early as 3 months (Yoshiyama

et al., 2007). Increased inflammatory factors in CA3 region

and synaptic dysfunction in CA1 region of the hippocampus

occurred at 4 and 6 months, respectively (Yoshiyama et al.,

2007). NFTs were observed in the neocortex, amygdala,

hippocampus, brain stem and spinal cord at 6 months with

progressive accumulation (Yoshiyama et al., 2007). Astro-

gliosis was seen in white and gray matter of hippocampus,

amygdala, entorhinal cortex, and spinal cord at 6 months

(Yoshiyama et al., 2007). At 6 months of age, the mice

showed a variety of cognitive impairments, including

working memory, spatial learning and memory, contextual

memory, sociability, and object recognition (Takeuchi et al.,

2011). Neuron loss in the hippocampus at 8 months, and in

the entorhinal cortex, piriform cortex and amygdala at

12 months (Yoshiyama et al., 2007). Remarkable atrophy of

hippocampus and entorhinal cortex plus ventricular dilata-

tion were detected at 9 months (Yoshiyama et al., 2007). 80%

PS19 mice died by 12 months (Yoshiyama et al., 2007). This

model has been used to evaluate the therapeutic effect of

metformin, tryptophan-tyrosine-related β-lactopeptides,

ibrutinib on tau pathology and tau-related cognitive impair-

ment (Ano et al., 2023;Lee et al., 2021a;Zhao et al., 2023).

Studies have also combined this model with AD risk factors,

such as Aβ42, APOE and TREM2, to study their effects on

tau pathology (Gratuze et al., 2020;Williams et al., 2022;

Zampar and Wirths, 2021).

Other AD-related single gene mouse models

Some single gene mouse models carrying AD-related genes

with AD pathological change and cognitive impairment are

summarized in Table 4 (Heckmann et al., 2020;Pensalfini et

al., 2020;Plucińska et al., 2014;Zhong et al., 2022). These

genetically modified models in the background of murine

APP can cause AD-related pathological changes and cog-

nitive impairment, thus are important to elucidate novel AD

pathogenesis and potential therapeutic targets such as au-

tophagy, neuroinflammation, endosomal dysfunction, cal-

cium dysregulation, and palmitoylation.

ATG16L encodes the part of a large protein complex that is

necessary for autophagy, and its expression level is down-

regulated in AD patients (Heckmann et al., 2020). Mice

lacking the WD domain of ATG16L showed age-associated

development of AD pathologies, such as Aβ deposits, tau

hyperphosphorylation, neurodegeneration, microgliosis,

neuroinflammation, and impaired synaptic plasticity.

MCC095, a brain-penetrant inflammasome inhibitor, ame-

liorated AD pathology and cognitive impairment in ATG16L

mice (Heckmann et al., 2020). BACE1 encodes β-site APP

cleaving enzyme 1, which directly relates to Aβ plaque

formation and APP metabolism. The PLB4 (hBACE1) mice

12 Li, X., et al. Sci China Life Sci

Table 4 Characteristics of other AD-related gene mouse modelsa)

Gene Model name Aβ Tau Neuronal damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive

dysfunction References

ATG16L Atg16LΔWD

Elevated extracellar

and intraneural Aβ,

but no plaque at

2 years.

Pervasive

hyperphosphorylation

of microtubule-stabilizing

protein tau in

hippocampus with

pronounced accumulation

in CA3 field at 2 years.

Apoptotic death,

apoptosis and

suggestive of active

neurodegeneration,

reduction in total

neurons within

hippocampus at

2 years.

exacerbated

activation of

microglia in

hippocampi at

2 years.

—

substantial

reduction in LTP

at CA3-CA1

synapses at

2 years.

Impaired

performances in

sucrose preference

test, Y-maze, and

NOR at 2 years.

(Heckmann et al.,

2020)

BACE1 PLB4

(hBACE1)

Elevated

extracellular and

intraneural Aβ at

12 months; plaques

virtually absent,

minimal small

sparse plaques;

extracellular Aβ

staining includes

Aβ multimers.

Preliminary analysis did

not find abnormal

phosphorylation or

conformational changes

in tau. Increase trends

of total tau levels at

6 months.

—

Increased

astrogliosis in DG,

CA1 region of

hippocampus, and

piriform cortex at

12 months. Gliosis

is suspected to

begin earlier than

12 months.

— —

Impaired spatial

representation in a

habituation task at

3 months; impaired

learning and

memory in Y-maze,

MWM, and a test

of social transmis-

sion of food pre-

ference at

6 months.

(Plucińska et al.,

2014)

GluN3A GluN3A KO

Significant

depositions of

endogenous Aβ

overlaid with

neurons in

hippocampus at

10–15 months.

Increased total tau

expression in cortex at

6–7 months; tau

hyperphosphorylation in

both hippocampus and

cortex at 10–15 months.

Neurodegeneration

of olfactory sensory

neurons at 2–3 months;

neuron loss in olfactory

bulb and hippocampal

CA3 region at

10–12 months;

increased apoptotic

marker cleaved by

caspase-3 in cortex

at 10–12 months.

Reactive astrocytes

in hippocampus

at 10–15 months.

Decreased level of

synapsin in

hippocampus at

7 months; no

significant

difference in ex-

pression of

synaptophysin and

PSD-95.

Enhanced LTP in

hippocampus at

2–4 months;

suppressed LTP

in hippocampus

at 6–7 months.

Impaired

recognition mem-

ory and slower

learning at

5–6 months;

impaired spatial

working memory

at 7 months; poor

social novelty

performance at

5–12 months.

(Zhong et al., 2022)

Rab5a PA-Rab5 —

Levels of total tau and

tau hyperphosphorylation

are increased in cortices

at 15 months.

Loss of basal forebrain

cholinergic neurons

started at 7 months;

abnormal swelling and

thickening of proximal

dendrites and dys-

morphic cell bodies.

—

Loss of spines in

CA3 and DG

regions of

hippocampus at

8.5 months, but not

in CA1 region.

Defect in LTD and

slight impairment

in LTP in hippo-

campal slices at

Schaffer collateral-

CA1

synapses from

6 months.

Reduced retention

in NOR test in

6-month-old

mice.

(Pensalfini et al.,

2020)

ZDHHC21 ZDHHC21

T209S KI

Increased

intraneural Aβ42

in hippocampus

at 9 months

Phosphorylated tau

aggregates in

hippocampus at

9 months.

Neuronal loss in

hippocampus at

9 months. —

Decreased synapse

density in hippo-

campus at

6 months; reduced

number of dendritic

branches and

spines in

hippocampus at

9 months.

Reduced LTP in

hippocampus at

3 months

Impaired spatial

learning and

memory ability in

MWM at

9 months.

(Li et al., 2023)

a) The table is ordered by mutation site alphabetically. “—” means no data.

Li, X., et al. Sci China Life Sci

showed accumulation of Aβ56 and Aβ hexamers without

plaques, gliosis, neuroinflammation and cognitive impair-

ment relevant to AD, which suggests that mouse APP can be

cleaved by human BACE1 (Plucińska et al., 2014). GluN3A

encodes a subunit of the NMDA receptors that belong to the

superfamily of glutamate-regulated ion channels, and func-

tions in physiological and pathological processes in the

central nervous system (Zhong et al., 2022). GluN3A KO

mice developed olfactory dysfunction followed by cognitive

deficits prior to Aβ and tau pathology, and also showed

neuronal hyperactivity, calcium dysregulation, neuroin-

flammation, impaired synaptic plasticity and neuronal loss

(Zhong et al., 2022). Rab5 is a small GTPase that regulates

endosome trafficking, sorting, and fusion and involves Aβ

clearance. Rab5-mediated endosomal dysfunction occurs

very early in AD. Overexpressing human Rab5 in mice

neuron led to tau hyperphosphorylation, basal forebrain

cholinergic neurodegeneration, impaired LTP and LDP,

hippocampal spine abnormalities, endosomal dysfunction

and memory deficits (Pensalfini et al., 2020). ZDHHC21

encodes zinc finger DHHC-type palmitoyltransferase 21,

and enables palmitoyltransferase activity (Pedram et al.,

2012). The T209S mutation of ZDHHC21 was found in a

Han Chinese family with AD. Homozygous mice carrying

this mutation showed elevated palmitoylation of APP and

Fyn, resulting in AD-related pathologies including Aβ ac-

cumulation, tau hyperphosphorylation, deficits in LTP, de-

creased dendritic spines and branches, and cognitive

impairment (Li et al., 2023).

Heterogeneity in single transgenic mouse models

Taken together, most PSENs transgenic models are lack of

gliosis or synaptic changes, except PS1V97L Tg mice. Most

APP transgenic models are lack of tau tangles and neuronal

damages. None of the PSENs or MAPT transgenic models

show Aβ plaques. The possible reasons for lacking Aβ pla-

ques might be due to the differences between mouse and

human APP. Studies have shown that when mice over-

expressing or knocking in human PSEN1 mutation are bred

with human APP mutant mice, plaque deposition begins at

an earlier age and increases with aging as compared to the

parental APP lines (Borchelt et al., 1997;Dewachter et al.,

2000;Elder et al., 2010;Holcomb et al., 1998;Lamb et al.,

1999;McGowan et al., 1999). These data indicate that a

human APP might be necessary for the formation of Aβ

plaques.

Figure 2 shows the ethnic origin of AD pathogenic gene

mutation sites used in all AD mouse models, including APP,

PSENs and ZDHHC21. Three mutations have been reported

only in Asian, namely APP E693Δ(Osaka) mutation from

two Japanese AD families (Tomiyama and Shimada, 2020),

PSEN1 V97L mutation (Jia et al., 2005) and ZDHHC21

T209S mutation (Li et al., 2023) from two Chinese AD fa-

milies. These three mutations have been used to construct

mouse models to explore genetic mechanism and drug

treatment (Tomiyama et al., 2010;Wang et al., 2016), and

provide new ideas and therapeutic targets for AD drug de-

velopment. Two mutations have been reported only in

American or European populations, including APP KM670/

671NL (Swedish) mutation from two Sweden families

(Mullan et al., 1992) and APP I716V (Florida) mutation from

one American family. APP KM670/671NL (Swedish) mu-

tation is the most commonly used mutation to establish

mouse models, which can promote plaque formation and

cognitive impairment, and BACE1 was confirmed as a key

driver of AD and responsible for plaque formation based on

these mutant mouse models (Armbrust et al., 2022). How-

ever, clinical trials of BACE1 inhibitors have all failed, and it

is necessary to rethink the importance of N-terminal trun-

cated Aβ species and alternative β-secretases as therapeutic

targets (Armbrust et al., 2022). APP KM670/671NL

(Swedish) and I716V (Florida) were both used in the con-

struction of 5×FAD mice, the most commonly used mouse

models for AD. However, it is unknown whether the po-

tential mechanisms revealed by these mutant mouse models

are unique to each racial/ethnic group or apply to other ra-

cial/ethnic groups as well, which needs further research and

verification.

Comparisons between multi-transgenic mouse

models

Multi-transgenic mouse models with more than one patho-

logical and cognitive changes are summarized in Table 5

(Adalbert et al., 2009;Arancio et al., 2004;Arendash et al.,

2001;Baglietto-Vargas et al., 2021;Bellucci et al., 2007;

Billings et al., 2005;Borchelt et al., 1997;Borchelt et al.,

1996;Bouter et al., 2013;Brautigam et al., 2012;Breyhan et

al., 2009;Buskila et al., 2013;Cacciottolo et al., 2021;

Caruso et al., 2013;Casas et al., 2004;Cheng-Hathaway et

al., 2018;Cheng et al., 2004;Cheng et al., 2007;Chishti et

al., 2001;Codita et al., 2010;Colton et al., 2008;Crouzin et

al., 2013;Davis et al., 2004;Davis et al., 2006;Dewachter et

al., 2000;Domnitz et al., 2005;Dudal et al., 2004;Flanigan

et al., 2014;Garcia-Alloza et al., 2006;Gengler et al., 2010;

Giannoni et al., 2016;Gordon et al., 2002;Gratuze et al.,

2020;Grueninger et al., 2010;Hashimoto et al., 2019;Havas

et al., 2011;Holcomb et al., 1998;Hong et al., 2016;Howlett

et al., 2008;Howlett et al., 2004;Hsia et al., 1999;Hu et al.,

2018;Hyman and Tanzi, 2019;Jackson et al., 2013;Jackson

et al., 2016;Jankowsky et al., 2004;Jankowsky et al., 2005;

Jankowsky et al., 2001;Jawhar et al., 2012;Jay et al., 2017;

Kamphuis et al., 2012;Kang et al., 2021;Kim and Jeong,

2015;Kimura et al., 2012;Kimura and Ohno, 2009;Kno-

14 Li, X., et al. Sci China Life Sci

Table 5 Characteristics of AD mouse model with multiple gene mutationsa)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APOE,

APP,

PSEN1

APP KM670/671NL

(Swedish), I716V

(Florida), V717I

(London); PSEN1

M146L (A>C),

L286V

E2FAD Plaques at 4 months and

increase with age. — —

Microgliosis and

astrocytosis in

subiculum and

cortex at

6 months.

Decreased synap-

tic proteins of

NMDA receptor

subunits at

2–6 months.

—

Better than E4FAD

mice, and compar-

able to E3FAD mice

in Y maze and

MWM.

(Youmans et al.,

2012)

E3FAD

Plaques at 4 months and

increase with age; in-

creased Aβ deposits

primarily in cerebral

blood vessels at

6 months.

— —

Microgliosis and

astrocytosis in

subiculum and

cortex at

6 months.

Decreased synap-

tic proteins of

NMDA receptor

subunits at

2–6 months.

—

Better than E4FAD

mice, and compar-

able to E2FAD mice

in Y maze and

MWM.

(Cacciottolo et

al., 2021;You-

mans et al., 2012)

E4FAD

Plaques at 4 months and

increase with age; in-

creased Aβ deposits

primarily in cerebral

blood vessels at

6 months.

— —

Microgliosis and

astrocytosis in

subiculum and

cortex at

6 months.

Decreased protein

levels of PSD95

and NMDA re-

ceptor subunits by

4 months.

—

Learning deficits in

MWM by

2 months; progres-

sive decrease in

learning and mem-

ory tasks.

(Cacciottolo et

al., 2021;You-

mans et al., 2012)

APP

Aβ4-42 sequence

fused to murine thyr-

otropin-releasing hor-

mone (TRH) signal

peptide

Tg4-42

No plaques; Aβ4-42

expression in hippo-

campal CA1 region and

detectable around

2 months.

Absent.

Age- and dose-de-

pendent hippocam-

pal neuronal loss

in CA1 region;

hemizygotes had

38% neuronal loss

at 8 months, and

49% loss at

12 months.

Reactive micro-

glia and astro-

cytes in

hippocampus at

2 months.

Altered synapto-

physin staining in

hippocampal CA3

region at

8 months.

—

Age-dependent spa-

tial learning deficit

in MWM at

8 months; impaired

contextual fear con-

ditioning at

12 months.

(Bouter et al.,

2013)

APP KM670/671NL

(Swedish), S679C TgDimer Intracellular Aβ depos-

its in hippocampus and

cortex at 12 months.

Absent through

24 months. Absent through

24 months. —

Impaired LTP in

Schaffer collat-

eral-CA1 synaptic

system at

6–8 months.

Learning deficits in

MWM at 7 months. (Müller-Schiff-

mann et al., 2016)

APP KM670/671NL

(Swedish), E693G

(Arctic) ArcAβ

Intracellular punctate

Aβ deposits in cortex

and hippocampus;

abundant plaques by

9–15 months.

Absent. — — —

Impaired LTP in

hippocampus

slices at 3.5–7.5

months.

Cognitive impair-

ment in MWM and

Y maze at

6 months.

(Knobloch et al.,

2007a;Knobloch

et al., 2007b)

APP KM670/671NL

(Swedish), E693G

(Arctic) Tg-ArcSwe

Extracellular amyloid

plaque deposition starts

at around 5–6 months in

cortex, hippocampus,

and thalamus; CAA in

cerebral cortical vessels

at 12 months.

Absent. Absent.

Microgliosis and

astrogliosis most

prominent in hip-

pocampus, also

around deposits in

cortex and thala-

mus.

— —

Spatial learning im-

pairment in MWM

at 4–8 months and

in passive avoid-

ance test at

16 months.

(Codita et al.,

2010;Lillehaug et

al., 2014;Lord et

al., 2009;Lord et

al., 2006;Skaar-

aas et al., 2021)

APP KM670/671NL

(Swedish), E693Q

(Dutch), D694N

(Iowa)

Tg-SwDI

(APP-Swedish,

Dutch, Iowa)

Aβ deposits in subicu-

lum, hippocampus and

cortex at 3 months;

more numerous at

6 months; throughout

most forebrain by

12 months; microvascu-

lar amyloid deposits at

24 months.

Absent. —

Pronounced in-

creased astrocytes

and activated mi-

croglia at

6–24 months

especially in tha-

lamus and subi-

culum.

— —

Impaired learning

and memory in

Barnes maze task at

3, 9, and 12 months.

(Davis et al.,

2004;Davis et al.,

2006;Miao et al.,

2005b;Xu et al.,

2007)

(To be continued on the next page)

Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP

APP KM670/671NL

(Swedish), T714I

(Austrian)

A7 APP

transgenic

Amyloid deposition in

cortex at 9–12 months;

extensive deposition at

21 months.

— — — — — — (Yamada et al.,

2009)

APP KM670/671NL

(Swedish), V717F

(Indiana)

J20 (PDGF-

APPSw, Ind)

Diffuse Aβ plaques in

DG and neocortex at

5–7 months; widespread

plaques by

8–10 months.

Absent.

Decreased neuronal

numbers in hippo-

campal CA1 region

at 3, 6 and

9 months.

Significant in-

crease in the

number of astro-

cytes and micro-

glia in

hippocampus at

4–6 months

Loss of hippocam-

pal synaptophysin,

synaptotagmin,

PSD-95 and homer

immunoreactivity

by 3 months; im-

paired basal sy-

naptic transmission

at 3–6 months.

Impaired LTP at

Schaffer collat-

eral-CA1 synapse

at 3–6 months.

Spatial reference

memory deficits as

measured by RAM

and MWM at

4 months.

(Cheng et al.,

2007;Hong et al.,

2016;Mucke et

al., 2000;Wright

et al., 2013)

PDGF-APPSw,

Ind (line J9)

20% had plaques at

5–7 months, 50% at

8–10 months, and 100%

by 21–25 months.

— — — Deficits in synap-

tic transmission at

2–4 months. — — (Hsia et al., 1999;

Mucke et al.,

2000)

TetO-APPS-

weInd (line

102, 107, 885)

Progressive amyloid

plaques at 2 months;

extensive amyloid

pathology in cortex and

hippocampus by

9 months.

— — — — — — (Jankowsky et al.,

2005)

TgCRND8

Amyloid deposition at

3 months; plaques by

5 months; first in sub-

iculum, amygdala and

frontal cortex; severe

vascular Aβ deposition

at 11 months.

Absent of NFTs;

hyperphosphory-

lated, nitrosy-

lated and

aggregated tau at

7–12 months

especially in

neocortex, DG,

and hippocampal

CA1/CA3 areas.

Neuritic pathology

by 5 months; fewer

hippocampal neu-

rons at 6 months.

Microglia activa-

tion and robust

astrogliosis in

cortex and hippo-

campus by

3 months; numer-

ous by 5 months.

Reduced synapto-

physin immunor-

eactivity at

6 months; re-

duced excitatory

synaptic trans-

mission at

6–12 months.

Reduced LTP in

hippocampal

slices at 6–12

months.

Impaired acquisi-

tion and reversal

learning in MWM

at 3 months.

(Adalbert et al.,

2009;Bellucci et

al., 2007;Brauti-

gam et al., 2012;

Chishti et al.,

2001;Domnitz et

al., 2005;Dudal

et al., 2004;Ki-

mura et al., 2012)

APP KM670/671NL

(Swedish), V717F

(Indiana), E693G

(Arctic)

Arc48 (APPSw/

Ind/Arc)

Parenchymal neuritic

plaques by 2 months;

prominent hippocampal

plaques by 3–4 months;

abundant plaques by

10–12 months.

Absent. Dystrophic neurites

by 10–12 months.

Reactive astrocy-

tosis at

3–4 months in

DG.

— —

Impaired ability to

use extramaze cues

to navigate to the

hidden platform in

MWM at 3–4

months

(Cheng et al.,

2004;Cheng et

al., 2007)

APP KM670/671NL

(Swedish), V717I

(London)

APPSweLon Increased Aβ42 at

3–4 months; no amyloid

deposits by 24 months. — — — — — — (Lamb et al.,

1999;Lamb et al.,

1997)

mThy1-

hAPP751

(TASD41)

Increased Aβ40, Aβ42

and AβOs at 6 months;

plaques at 3–6 months

in frontal cortex.

Absent. Dystrophic neurites

at 12 months.

Inflammation re-

lated to activated

microglia and re-

active astrocytes

by 6 months.

Synaptic loss at

12 months. —Learning and mem-

ory deficits in

MWM at 6 months.

(Havas et al.,

2011;Rocken-

stein et al., 2001;

Rockenstein et

al., 2005)

rTg9191

Plaques in cerebral cor-

tex at 8 months; in hip-

pocampus at 10.5–

12.5 months.

Hyperpho-

sphorylated tau

develops with

age.

Reduced forebrain

weight and smaller

DG at 2–6 months.

Astrocytosis and

microgliosis near

plaques at

24 months.

— — Absent. (Liu et al., 2015)

(To be continued on the next page)

16 Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP

Glutamate at position

three of Aβ amino

acid sequence was

mutated into gluta-

mine

TBA42

Aβ accumulates in hip-

pocampal neurons at

3 months and cerebellar

nuclei by 6 months; Aβ

(pE3-42) accumulates in

spinal cord and pyrami-

dal neurons of motor

cortex at 12 months.

Absent.

35% neuronal loss

in hippocampal

CA1 region at

12 months.

Marked gliosis in

hippocampus at

12 months. — —

Working and spatial

reference memory

deficits at

12 months.

(Wittnam et al.,

2012)

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H)

hAβ-KI

Decreased soluble Aβ

and increased insoluble

Aβ; no plaques up to

22 months.

Absent.

No cell loss in pyr-

amidal layer of hip-

pocampal CA1

region, but signifi-

cant hippocampal

volume differences at

22 months

Astrocytosis in

hippocampus at

22 months.

Reduction of sy-

naptophysin and

PSD95 expres-

sion in hippo-

campus at

18 months.

Impaired LTP at

18 months.

Cognitive impair-

ment in contextual

fear conditioning at

10 months, and

NOR at 14 months.

(Baglietto-Vargas

et al., 2021)

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP

KM670/671NL

(Swedish)

APPSwe (line

C3-3)

Aβ deposition at

18–20 months; plaques

formation at

24–26 months.

—— ———Absent at

12-14 months. (Savonenko et al.,

2003)

APPSwe (line

E1-2)

Aβ increase slightly at

6–14 months, and sig-

nificantly at

24–26 months.

—— ———Cognitive deficits at

12-13 months. (Savonenko et al.,

2003)

TgAPPSwe-KI

Absent of mouse de-

rived Aβ overexpres-

sion; increased human

derived Aβ deposition.

— — — — — — (Reaume et al.,

1996)

Humanize mouse Aβ

region: G676R (G5R),

F681Y (F10Y),

R684H (R13H); APP

KM670/671NL

(Swedish), E693G

(Arctic), T714I (Aus-

trian)

AppSAA KI

Increased Aβ42 to 40

ratio in brain, CSF and

plasma at 2 months;

plaques in homozygotes

at 4 months, most pro-

nounced in cortex and

hippocampus.

No NFTs at

8 months; in-

creased CSF

total tau in

homozygotes at

8 months.

AT8-positive dys-

trophic neurites in

homozygous mice

at 8 months.

Plaque-associated

microgliosis at

4 months. — — — (Xia et al., 2021)

Humanize mouse Aβ

region: G676R (G5R),

F681Y (F10Y),

R684H (R13H); APP

KM670/671NL

(Swedish), E693G

(Arctic), I716F (Iber-

ian)

APPNL-G-F KI Plaques at 2 months

with near saturation by

7 months.

No tangles; ele-

vated levels of

phosphorylated

tau in dys-

trophic neur-

ites.

Dystrophic neurites

Microglia and ac-

tivated astrocytes

accumulate at

2 months, concur-

rent with plaque

formation.

Changes in synap-

tic microstructure

and reduction of

synaptophysin and

PSD95 immunor-

eactivities in cor-

tices and

hippocampus at

6 months.

—

Memory impair-

ment in Y maze test

at 6 months, and in

NOR at 9 months.

(Liu et al., 2021b;

Mehla et al.,

2019;Nilsson et

al., 2014;Saito et

al., 2014)

Humanize mouse Aβ

region: G676R (G5R),

F681Y (F10Y),

R684H (R13H); APP

KM670/671NL

(Swedish), I716F

(Iberian)

APPNL-F KI

Increased Aβ42/Aβ40

ratio and plaques in

cortex and hippocampus

at 6 months.

Elevated phos-

phorylated tau

in dystrophic

neurites at

6 months.

Dystrophic neurites

at 6 months.

Microglia and ac-

tivated astrocytes

accumulate at

6 months, concur-

rent with plaque

formation.

Reduced synapto-

physin and

PSD95 immunor-

eactivities at

9–12 months.

—

Memory impair-

ment in Y maze at

18 months; absent

in MWM at

18 months.

(Saito et al.,

2014)

(To be continued on the next page)

Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP E693G

(Arctic), I716F (Iber-

ian)

AppG-F KI

Aβ deposition in the

cortex at 4–6 months, in

the hippocampus at

8–12 months.

— —

Reactive astro-

cyte and activated

microglia around

plaques in the

cortex at

22 months.

Decreased synap-

tophysin and

postsynaptic den-

sity protein 95

immunoreactivity

in hippocampus at

22 months.

— — (Watamura et al.,

2022b)

APP,

BACE1,

PSEN1

APP KM670/671NL

(Swedish), I716V

(Florida), V717I

(London); PSEN1

M146L (A>C),

L286V

BACE1 cKO

(Hu, Yan)×5×-

FAD

Plaques accumulate up

to 4 months and even-

tually disappear. —

Dystrophic neurites

accumulate up to

4 months, to a lesser

degree than in con-

trol 5×FAD.

Reactive astro-

cytes and micro-

glia accumulate

up to 4 months.

—

Deficit in LTP at

Schaffer collat-

eral-CA1 sy-

napses by

10–12 months.

Normal contextual

and cued fear con-

ditioning at

8–10 months.

(Hu et al., 2018)

APP,

MAPT

APP KM670/671NL

(Swedish); MAPT

P301L

Tg2576/Tau

(P301L)

(APPSwe-Tau) Plaques at 6–7 months.

Tangles in

spinal cord and

pons at

3 months; in-

creased in lim-

bic areas by

6 months.

—

Reactive astro-

cytes and micro-

glia at 3 months

in hippocampus;

increased astrocy-

tosis in limbic

areas; microglia

around plaques at

9 and 12 months.

— — — (Lewis et al.,

2001)

Human Aβ4-42 se-

quence; MAPT P301S PS19/Tg4-

42hom Amyloid deposition at

3 months.

Phosphorylated

tau accumula-

tions at

3 months; abun-

dant tau pathol-

ogy with NFTs

in CA1 pyrami-

dal layer at

9 months.

Neuron loss in dis-

tal and proximal

CA1 at 3 months. ———

Impaired motor and

spatial learning at

5 months; impaired

recognition memory

at 9 months.

(Zampar and

Wirths, 2021)

Humanize mouse Aβ

region: G676R (G5R),

F681Y (F10Y), R684H

(R13H); APP KM670/

671NL (Swedish),

E693G (Arctic), I716F

(Iberian)

AppNL-G-F/

MAPT KI Plaques at 2 months. Absent. Absent. Astrogliosis and

microgliosis by

4 months. — — Working memory

deficits in Y-maze

at 12 months

(Hashimoto et al.,

2019;Saito et al.,

2019)

APP,

MAPT,

PSEN1

APP KM670/671NL

(Swedish); MAPT

P301L; PSEN1

M146V

3×Tg

Intraneuronal Aβ

pathology in hippocam-

pus, cortex and amyg-

dala at 4 months;

extracellular Aβ depos-

its in frontal cortex by

6 months.

Extensive tau

immunoreactiv-

ity in hippo-

campal CA1

pyramidal neu-

rons by

12 months, later

in cortex.

—

Increased density

of astrocytes and

microglia at

7 months.

Impaired basal

synaptic trans-

mission at

6 months

Decreased LTP at

6 months

Long-term retention

deficit at 4 months;

spatial learning and

memory deficit in

Barns maze at

6.5 months.

(Billings et al.,

2005;Caruso et

al., 2013;Oddo et

al., 2003;Stover

et al., 2015)

APP KM670/671NL

(Swedish), I716V

(Florida), V717I (Lon-

don); MAPT P301L;

PSEN1 M146L (A>C),

L286V

6×Tg

Aβ42 accumulation at

2 months; plaques in

cortex and hippocampus

at 4 months.

Hyperpho-

sphorylated tau

at 4 months;

develops with

age.

Neuronal loss in

cortex at 4 months

and in hippocampus

at 6 months.

Microglial activa-

tion in cortex and

hippocampus at

2 months.

Synaptic loss in

cortex from

4 months, and in

hippocampus

from 6 months.

—Decreased cognitive

and memory capa-

city at 2 months.

(Kang et al.,

2021)

(To be continued on the next page)

18 Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP,

MAPT,

PSEN1

APP KM670/671NL

(Swedish), V717I

(London); MAPT

P301L, R406W;

PSEN1 A246E

PLB1-triple

(hAPP/hTau/

hPS1)

Sparse plaques by

21 months; intracellular

Aβ accumulation and

formed oligomers.

Tau hyperpho-

sphorylation in

hippocampus

and cortex from

6 months.

—

Increased inflam-

mation at

12 months in cor-

tex and hippo-

campus.

Impaired synaptic

transmission at

12 months.

Reduced LTP and

paired-pulse fa-

cilitation at 6 and

12 months.

Reduced social re-

cognition at 5 and

12 months; object

recognition at

8 months spatial

learning at

12 months.

(Platt et al., 2011)

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP

KM670/671NL

(Swedish); PSEN1

deltaE9

APP/PS1/

rTg21221

Cortical plaques ob-

served between

8–10 months.

Aggregates of

misfolded and

phosphorylated

tau between

8–10 months.

Neuronal loss near

plaques. Astrocytosis near

plaques.

Decreased sy-

napse density

near plaques. — — (Jackson et al.,

2016)

APP,

MAPT,

PSEN2

APP KM670/671NL

(Swedish); MAPT

P301L; PSEN2 N141I TauPS2APP

Rare amyloid plaques at

4 months; increase in

subiculum and hippo-

campal CA1 region by

8 months.

Abnormally

phosphorylated

tau at 4 months,

in subiculum,

amygdala, and

hippocampal

CA1 region;

tangle-like de-

posits in hippo-

campus by

16 months.

Absent at

16 months. ———

Impaired spatial

learning in MWM

at 4 months, but not

progressive be-

tween 4 and

12 months, and in-

dependent of

pathology.

(Grueninger et al.,

2010)

APP,

NOS2

APP KM670/671NL

(Swedish), E693Q

(Dutch), D694N

(Iowa)

APPSwDI×-

NOS2 KO

Plaques especially in

thalamus and subicu-

lum.

Aggregated,

hyperpho-

sphorylated tau

tangles.

Neuronal loss in

hippocampus and

subiculum. ———

Learning and mem-

ory deficits mea-

sured by RAM and

Barnes maze at

12–13 months.

(Colton et al.,

2008;Wilcock et

al., 2008)

APP,

Pdgfrβ

APP KM670/671NL

(Swedish); Pdgfrβ

gene deleted

APPsw/0;

Pdgfrβ+/-

Elevated plaque load in

cortex and hippocampus

at 9 months.

Tau hyperpho-

sphorylation in

cortical and

hippocampal

neurons at

9 months.

Reduced neurite

density and neuro-

nal loss in cortex

and hippocampus at

9 months.

———

Impaired nest

building, burrow-

ing, and NOR at

9 months.

(Sagare et al.,

2013)

APP,

PSEN1

APP KM670/671NL

(Swedish), I716V

(Florida), V717I

(London); PSEN1

M146L (A>C),

L286V

5×FAD

(B6SJL)

Extracellular amyloid

deposition in cortex at

2 months; throughout

hippocampus and cortex

by 6 months.

Absent.

Neuron loss in cor-

tical layer 5 and

subiculum at

6 months.

Gliosis at

2 months.

Decreased presy-

naptic marker sy-

naptophysin by

4 months; de-

creased presynap-

tic marker syntaxin

and postsynaptic

marker PSD-95 by

9 months.

Deteriorated LTP

in hippocampal

CA1 at

4–6 months; defi-

cits in basal sy-

naptic transmis-

sion by 6 months.

Impaired spatial

working memory in

Y-maze and MWM

by 4–6 months;

impaired remote

memory

stabilization by

4–5 months;

impaired learning

at 9 months;

impaired social

recognition at

9–12 months.

(Crouzin et al.,

2013;Flanigan et

al., 2014;Kimura

and Ohno, 2009;

Oakley et al.,

2006;Xiao et al.,

2015)

(To be continued on the next page)

Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP,

PSEN1

APP KM670/671NL

(Swedish), I716V

(Florida), V717I

(London); PSEN1

M146L (A>C),

L286V

5×FAD

(C57BL6)

Plaques in hippocam-

pus, cortex, and thala-

mus at 2 months, and in

spinal cord by

3 months; progressive

CAA on leptomeningeal

and penetrating vessels

started at 3 months.

—40% neuron loss in

cortical layer V at

12 months.

Plaques asso-

ciated microglio-

sis and

astrogliosis; vas-

cular damage as-

sociated micro-

gliosis.

Reduced spine

density in pyra-

midal neurons in

somatosensory

and prefrontal

cortices at

6 months.

Layer V neurons

from 2–3 months

old mice have lost

the ability to un-

dergo LTP and

have a small yet

significant in-

crease in LTD

following spike-

timing-dependent

plasticity induc-

tion.

Impaired spatial

working memory at

3–6 months and

worsen with age.

(Buskila et al.,

2013;Giannoni et

al., 2016;Jawhar

et al., 2012;Ri-

chard et al., 2015)

AD-BXD Strain-dependent amy-

loid plaques by

6 months. — — Strain-dependent

gliosis by

6 months. — —

Impaired in contex-

tual fear condition-

ing at 14 months.

Age of onset and

severity of impair-

ment are strain-de-

pendent.

(Hyman and Tan-

zi, 2019)

APP KM670/671NL

(Swedish); PSEN1

M146L (A>C) PS/APP Aβ accumulate in cortex

and hippocampus at

6 months.

No tangles; hy-

perphosphory-

lated tau

detected at

6 months, near

amyloid depos-

its in the cortex

and hippocam-

pus.

Neuronal loss in

hippocampal CA1

region at

22 months.

Numbers of as-

trocytes increase

in the cortex;

numbers of rest-

ing microglia in-

crease in the

vicinity of depos-

its at 6 months.

— —

Reduced sponta-

neous alternation

performance in Y

maze at 3 months;

progressive cogni-

tive impairment as-

sessed by RAM.

(Arendash et al.,

2001;Gordon et

al., 2002;Hol-

comb et al., 1998;

Kurt et al., 2003;

Sadowski et al.,

2004)

APP KM670/671NL

(Swedish); PSEN1

M146V

ARTE10

Plaques by 3 months in

homozygotes and

5 months in hemizy-

gotes; start in anterior

neocortex and subicu-

lum.

No tangles; hy-

perphosphory-

lated tau in

dystrophic

neurites at

8 months.

Reduced dendritic

length, surface area,

and branches in

hippocampal neu-

rons at

10–14 months.

Reactive astro-

cytes and acti-

vated microglia

around plaques at

5 months in

homozygotes, la-

ter in hemizy-

gotes

Decreased ex-

pression of sy-

naptophysin

mRNA by

3–4 months

—

Cognitive deficits in

an object-recogni-

tion task and MWM

at 12 months.

(Willuweit et al.,

2009)

TASTPM

(TAS10×TPM)

Aβ deposit starts at

3 months; plaques evi-

dent by 6 months in

cortex and hippocam-

pus.

Absent.

Minimal neuronal

loss up to

10 months; some

signs of loss near

plaques in hippo-

campus.

Greater numbers

of reactive astro-

cytes and micro-

glia by 6 months

in hippocampus

and cortex.

— —

Age-dependent im-

pairment in object

recognition memory

at 6 months.

(Howlett et al.,

2008;Howlett et

al., 2004)

APP KM670/671NL

(Swedish); PSEN1

L166P APPPS1

Amyloid plaque

deposition in neocortex

at 1.5 months;

hippocampus at

3–4 months; striatum,

thalamus and

brainstem at

4–5 months.

Phosphorylated

tau-positive

neuritic pro-

cesses around

plaques.

Neuron loss in DG

and other subre-

gions with high

neuronal density at

17 months.

Activated micro-

glia and increased

astrogliosis at

1.5 months.

Dendritic spine

loss at 2.5 month.

Hippocampal

CA1 LTP im-

paired at 8 and

15 months

Spatial learning and

memory deficits in

MWM at 7 months;

impaired reversal

learning in four-arm

spatial maze at

8 months.

(Gengler et al.,

2010;Radde et

al., 2006;Rupp et

al., 2011)

(To be continued on the next page)

20 Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP,

PSEN1

APP KM670/671NL

(Swedish); PSEN1

R278I

APP23×PS1-

R278I

Elevated Aβ43 by

3 months; amyloid de-

position by 6 months in

cortex and hippocam-

pus; high density of

cored plaques.

Absent. —

Astrocytosis near

plaques in hippo-

campus and cor-

tex by 9 months.

— — Short-term memory

deficits in Y maze

by 3–4 months.

(Saito et al.,

2011)

APP KM670/671NL

(Swedish), V717I

(London); PSEN1

M233T, L235P

APP751SL/PS1

Aβ deposition at

2.5 months; compact

deposits in

hippocampus, cortex

and thalamus at

6 months.

—

Neuronal loss de-

tected in female

mice at 6 months; in

hippocampus CA1/

2 at 10 months.

Astrogliosis in

proximity of Aβ-

positive neurons

at 2.5 months.

Reduced pre- and

post-synaptic

markers are at

6 months.

Reduced LTP and

disrupted paired

pulse facilitation

at 6 months.

Impaired working

memory by Y maze

and T-maze at 6 and

12 months.

(Breyhan et al.,

2009;Casas et al.,

2004)

APP V717I (London);

PSEN1 A246E

APP

(V717I)×PS1

(A246E)

Soluble AβOs at

2 months; plaques in

cortex, hippocampus

and subiculum at

4–6 months; CAA

pathology at 8 months.

Hyperpho-

sphorylated

murine tau; no

tangles.

Dystrophic neurites.

Microglial activa-

tion and other

markers of brain

inflammation in-

crease at

4.5 months.

—

Significant deficit

in LTP in hippo-

campal CA1 re-

gion at 6 months.

Spatial and

non-spatial

orientation and

memory deficits

by MWM at

5 months;

impaired

associative

learning.

(Dewachter et al.,

2000)

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP

KM670/671NL

(Swedish), I716F

(Iberian); PSEN1

P117L

AppNL-F

Psen1P117L

double-mutant

Increased Aβ40, Aβ42

and Aβ43 in cortices at

3 months; dense cored

plaques at 12 months.

— —

Significantly mi-

crogliosis and as-

trocytosis in

hippocampus at

12 months.

— — — (Sato et al., 2021)

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP

KM670/671NL

(Swedish); PSEN1

A246E

APPSwe/

PSEN1(A246E)

Amyloid plaques in

hippocampus and subi-

culum by 9 months, la-

ter extending to the

cortex.

Absent. Absent. Gliosis in cortex

and hippocampus

at 12 months. — —

Age-associated

cognitive impair-

ment in MWM at

11–12 months.

(Borchelt et al.,

1997;Borchelt et

al., 1996;Puoli-

väli et al., 2002;

Wang et al., 2003)

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP

KM670/671NL

(Swedish); PSEN1

deltaE9

APPSwe/

PSEN1dE9

(C3-3×S-9)

Elevated Aβ42 and pla-

ques in hippocampus

and cortex at 6 months. Absent. — — — — Age-related cogni-

tive deficits at

18 months.

(Savonenko et al.,

2005)

APPswe/

PSEN1dE9

(C57BL6)

Plaques in cortex at

4 months and in

hippocampus at

6 months; amyloid

deposits on the

cerebral arteriole

wall at

7 months.

—Absent of neuron

loss up to

12 months.

Plaque-associated

astrogliosis and

microgliosis by 4

and 8 months, re-

spectively.

Synapse loss in

the hippocampus

by 4 months. —Deficits in MWM at

6–10 months and

worsen with age.

(Jackson et al.,

2013;Jankowsky

et al., 2001;Kim

and Jeong, 2015;

Malm et al.,

2007;Minkevi-

ciene et al., 2008)

(To be continued on the next page)

Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP,

PSEN1

Humanize mouse Aβ

region: G676R

(G5R), F681Y

(F10Y), R684H

(R13H); APP

KM670/671NL

(Swedish); PSEN1

deltaE9

APPswe/

PSEN1dE9

(line 85)

Occasional Aβ deposits

by 6 months; abundant

plaques in hippocampus

and cortex by 9 months;

progressive increase up

to 12 months.

Absent. Neuronal loss ob-

served adjacent to

plaques.

Minimal astrocy-

tosis at 3 months;

significant astro-

cytosis by

6 months; exten-

sive GFAP+

staining at

15 months.

Loss of

synaptophysin,

synaptotagmin,

PSD-95, and

homer immunor-

eactivity in

hippocampus by

4 months.

Reduced transient

LTP by 3 months;

not age related

from 3 to

12 months.

Deficits in spatial

memory in MWM

at 12 months.

(Garcia-Alloza et

al., 2006;Hong et

al., 2016;Jan-

kowsky et al.,

2004;Jankowsky

et al., 2001;

Kamphuis et al.,

2012;Lalonde et

al., 2005;Vo-

lianskis et al.,

2010)

CAST.APP/PS1

Plaques in cortex and

hippocampus by

8 months; more severe

in females.

Absent. Possible neuron loss

in hippocampal

CA1 area.

Plaque-associated

gliosis. — —

Impaired short-term

memory in Y-maze

in males, not avail-

able for females.

(Onos et al.,

2019)

PWK.APP/PS1 Plaques in the cortex

and hippocampal CA1

region by 8 months. Absent. Absent. Plaque-associated

microgliosis by

8 months. — — Absent assessed by

Y maze at

7–8 months.

(Onos et al.,

2019)

WSB.APP/PS1 Plaques in the cortex

and hippocampal CA1

region by 8 months. Absent. Fewer neurons in

cortex and CA1 of

female mice.

Plaque-associated

microgliosis by

8 months. — —

Deficits in short-

term memory by

8 months in female

mice.

(Onos et al.,

2019)

APP,

PSEN1,

TREM2

APP KM670/671NL

(Swedish), I716V

(Florida), V717I

(London); PSEN1

M146L (A>C),

L286V

TREM2-

BAC×5×FAD Plaques at 7 months. — — Microgliosis at

7 months. — — Absent (Lee et al., 2018)

Trem2 KO

(Colonna)×5×-

FAD Plaques at 4 months. — Loss of cortical

layer V neurons at

8 months.

Microgliosis at

4 months. — — — (Wang et al.,

2015)

TREM2, huma-

nized (common

variant)×5×-

FAD

Plaques at 8.5 months. — — Microgliosis at

8.5 months. — — — (Song et al.,

2018)

APP KM670/671NL

(Swedish), I716V

(Florida), V717I

(London); PSEN1

M146L (A>C),

L286V; TREM2

R47H

TREM2, huma-

nized

(R47H)×5×FA-

Plaques at 8.5 months — —

Lower density of

activated micro-

glia surrounding

plaques at

8.5 months.

— — — (Song et al.,

2018)

APP KM670/671NL

(Swedish); PSEN1

L166P

Trem2 KO

(KOM-

P)×APPPS1

Plaques observed by

2 months. — — Gliosis observed

by 2 months. — — — (Jay et al., 2017)

APP KM670/671NL

(Swedish); PSEN1

L166P; TREM2 R47H

Trem2 R47H

KI (Lamb/

Landreth)×

APPPS1-21

Plaques observed at

4 months.

No tangles;

hyperpho-

sphorylated

tau detected at

4 months;

Dystrophic neurites

surrounding plaques

at 4 months — — — — (Cheng-Hathaway

et al., 2018)

(To be continued on the next page)

22 Li, X., et al. Sci China Life Sci

(Continued)

Gene Mutation site Model name Aβ Tau Neuronal

damage Gliosis Synaptic changes Changes in

LTP/LTD Cognitive dysfunc-

tion References

APP,

PSEN2

APP KM670/671NL

(Swedish); PSEN2

N141I

PS2APP

Aβ deposition at

6 months; heavy plaque

load in hippocampus,

frontal cortex, and sub-

iculum at 10 months.

Absent. — Gliosis at

6 months. —

A strong increase

in LTP in hippo-

campal slices at

10 months.

Cognitive impair-

ment in MWM at 8

and 12 months.

(Ozmen et al.,

2009;Poirier et

al., 2010;Wei-

densteiner et al.,

2009)

PS2APP (PS2

(N141I)×APPs-

we)

Rare amyloid deposits

at 5 months; consistent

deposits in subiculum

and frontolateral cor-

tices by 9 months; pla-

ques spread throughout

neocortex, hippocam-

pus, amygdala, thalamic

and pontine nuclei at

17 months.

Absent. — Activated micro-

glia and astro-

cytes at 9 months. —Absent at 3 and

10 months.

Impaired acquisi-

tion of spatial

learning in MWM

from 8 months.

(Richards et al.,

2003)

APP,

RAGE

APP KM670/671NL

(Swedish), V717F

(Indiana)

Tg-mAPP/

RAGE — — —

Increased activa-

tion of microglia

and astrocytes at

14–18 months.

Decreased LTP at

8–10 months. —Impaired spatial

learning and mem-

ory at 3–4 months.

(Arancio et al.,

2004)

MAPT,

TREM2

MAPT P301S

PS19 with hu-

manized

TREM2 (com-

mon variant)

—Tangles at

9 months.

Atrophy of hippo-

campus and entorh-

inal/piriform cortex

and pronounced

ventricular expan-

sion at 9 months;

thinner DG granule

cell layer and piri-

form cortex pyra-

midal cell layer

compared to those

carrying R47H var-

iant of TREM2.

Elevated expres-

sion of markers of

astroglial and mi-

croglial reactivity,

compared with

those carrying the

R47H variant of

TREM2 at

9 months.

Fewer synapses

and more dys-

trophic synapses

compared with

those carrying the

R47H variant of

TREM2 at

9 months.

— — (Gratuze et al.,

2020)

MAPT P301S;

TREM2 R47H

PS19 with hu-

manized

TREM2

(R47H)

—Tangles at

9 months — — — — — (Gratuze et al.,

2020)

(To be continued on the next page)

a) The table is ordered by gene and mutation site alphabetically. “—” means no data.

Li, X., et al. Sci China Life Sci

bloch et al., 2007a;Knobloch et al., 2007b;Kurt et al., 2003;

Lalonde et al., 2005;Lamb et al., 1999;Lamb et al., 1997;

Lee et al., 2018;Lewis et al., 2001;Lillehaug et al., 2014;

Liu et al., 2015;Liu et al., 2021b;Lord et al., 2009;Lord et

al., 2006;Malm et al., 2007;Mehla et al., 2019;Miao et al.,

2005b;Minkeviciene et al., 2008;Mucke et al., 2000;Mül-

ler-Schiffmann et al., 2016;Nilsson et al., 2014;Oakley et

al., 2006;Oddo et al., 2003;Onos et al., 2019;Ozmen et al.,

2009;Platt et al., 2011;Poirier et al., 2010;Puoliväli et al.,

2002;Radde et al., 2006;Reaume et al., 1996;Richard et al.,

2015;Richards et al., 2003;Rockenstein et al., 2001;

Rockenstein et al., 2005;Rupp et al., 2011;Sadowski et al.,

2004;Sagare et al., 2013;Saito et al., 2014;Saito et al., 2019;

Saito et al., 2011;Sato et al., 2021;Savonenko et al., 2005;

Savonenko et al., 2003;Skaaraas et al., 2021;Song et al.,

2018;Stover et al., 2015;Volianskis et al., 2010;Wang et al.,

2003;Wang et al., 2015;Watamura et al., 2022b;Weiden-

steiner et al., 2009;Wilcock et al., 2008;Willuweit et al.,

2009;Wittnam et al., 2012;Wright et al., 2013;Xia et al.,

2021;Xiao et al., 2015;Xu et al., 2007;Yamada et al., 2009;

Youmans et al., 2012;Zampar and Wirths, 2021). These

models show different timelines and severity of AD-related

phenotypes. The mouse models carrying multiple mutants of

APP showed Aβ deposits and cognitive deficits, but absent

of NFTs and neuronal death. Mouse models carrying a

combination of APP and other gene mutations (such as

PSEN1,PSEN2,MAPT) exhibited earlier and more ag-

gressive pathological and behavioral changes than those only

carrying APP mutants. In addition, some multi-transgenic

mouse models also introduced risk genes such as APOE,

TREM2,ABCA7 and SORL1. To study the role of the three

human isoforms of APOE on AD phenotypes, APOE4,

APOE3, and APOE2 targeted replacement mice were crossed

with 5×FAD mice, respectively. Among them, E4FAD

mouse model carrying the APOE ε4 subtype had more pla-

ques and worse cognitive impairment than E3FAD and

E2FAD mice carrying APOE ε3 and APOE ε2 subtypes,

respectively (Youmans et al., 2012). TREM2 R47H was re-

ported as a significant risk modifier for late-onset AD, and

was constructed into the 5×FAD, APP/PS1-21 and PS19

mouse models. These mice carrying the TREM2 R47H mu-

tation had less pathology than those carrying wild type or

common variant of human TREM2 (Cheng-Hathaway et al.,

2018;Gratuze et al., 2020;Song et al., 2018). Other AD risk

genes mouse models such as Trem2 R47H KI×APOE4,

Abca7*A1527G/APOE4/Trem2*R47H, Sorl1*A528T/

APOE4/Trem2*R47H were not listed in the table due to lack

of pathological and cognitive evidence.

Figure 2 The ethnic origin of AD pathogenic gene mutation sites used in all single-transgenic AD mouse models. A, Number of single mutation sites found

in FAD in each continent. B, Overlaps of single mutation sites used in single-transgenic AD mouse models among continents.

24 Li, X., et al. Sci China Life Sci

Tg-SwDI mice

Tg-SwDI mice were constructed by random transgenic

technology and overexpressing the human APP gene (iso-

form 770) containing the K670N/M671L (Swedish), E693Q

(Dutch), and D694N (Iowa) mutations under the control of

the mouse Thy1 promoter (Davis et al., 2004). At 3 months

of age, insoluble Aβ deposits were found in the subcortex,

hippocampus and cortex of Tg-SwDI mice. By 6 months, Aβ

plaques-like deposits became more numerous and appeared

in the olfactory bulb and thalamus, and fibrillary Aβ accu-

mulation increased in the cerebral microvasculature. At

12 months, Aβ deposits were detected throughout the fore-

brain (Davis et al., 2004). The mice developed gliosis with

age (6–24 months) especially in the thalamus and sub-

iculum, and to a lesser extent in the cortex. Learning and

memory deficits were observed in the Barnes maze task at

3 months. This model serves as a cerebral microvascular

amyloid model for AD drug research, such as cGMP-grade

AV-1959D vaccine (Petrushina et al., 2020), taxifolin (Saito

et al., 2017), and minocycline (Fan et al., 2007).

J20 mice

J20 mice were constructed by random transgenic technology

and overexpressing the human APP gene containing the

K670N/M671L (Swedish) and V717F (Indiana) mutations

driven by the PDGF promoter (Mucke et al., 2000). The

expression of human APP in the brain of J20 mice was

moderate, but the accumulation of Aβ was the highest among

all PDGF-APP mice. Increased Aβ deposits in the hippo-

campus began at 1 month, and plaque formation started at

5–7 months (Mucke et al., 2000). hippocampal neuronal loss,

synapse loss and cognitive impairment were observed at

3 months (Cheng et al., 2007;Hong et al., 2016;Wright et

al., 2013). J20 mice also showed deficits in basal synaptic

transmission and LTP at the Schaffer collateral-CA1 synapse

at 3–6 months (Saganich et al., 2006), and developed mi-

crogliosis and astrogliosis in the hippocampus at 6–9 months

(Wright et al., 2013). In J20 mice, tumor necrosis factor

receptor 2 stimulation, adult neurogenesis modulation and

mTOR attenuation were found to be potential treatments for

AD (Ortí-Casañ et al., 2022;Van Skike et al., 2021;Zhang et

al., 2021).

TgCRND8 mice

TgCRND8 mice were constructed by random transgenic

technology and overexpressing the human APP gene (iso-

form 695) containing the K670N/M671L (Swedish) and

V717F (Indiana) mutations under the control of the hamster

prion gene promoter (Chishti et al., 2001). This model is an

early-onset AD model with Aβ deposition but no tangles.

The mice showed Aβ plaques, plaque-associated microglia

and astrocyte activation, and memory impairment at

3 months (Chishti et al., 2001;Dudal et al., 2004). Neuronal

loss, reduced LTP and decreased synaptophysin around the

plaques were seen in the hippocampus at 6 months (Adalbert

et al., 2009;Brautigam et al., 2012;Kimura et al., 2012). Tau

hyperphosphorylation and aggregation occurred at

7–12 months, particularly in neocortex and hippocampus

(Bellucci et al., 2007). Severe vascular Aβ deposition was

observed at 11 months (Domnitz et al., 2005). Nano-hono-

kiol, magnolol, and isorhynchophylline could ameliorate

neuropathology and cognitive deficits in TgCRND8 mice (Li

et al., 2019;Qu et al., 2022;Xian et al., 2020).

APPNL-G-F KI mice

APPNL-G-F KI mice were constructed by knocking in tech-

nology and humanizing mouse Aβ sequence and introducing

K670N/M671L (Swedish), E693G (Arctic), V716F (Beyr-

euther/Iberian) mutations into exon 16 and 17 of mouse APP

gene (Nilsson et al., 2014). In homozygous mice, elevated

levels of Aβ42 in the cortex started at 2 months, and plaques

appeared in the cortex, hippocampus and other subcortical

regions at 4 months (Saito et al., 2014). Gliosis, degenerative

neurons, decreased dendritic spines, reduced synaptophysin

and PSD95 associated with Aβ plaques, changes in the sy-

naptic microstructure, and impaired spatial learning and

memory in the MWM and Y maze were observed at

6 months (Liu et al., 2021b;Mehla et al., 2019;Nilsson et al.,

2014;Saito et al., 2014). Memory impairment in NOR trials

was observed at 9 months (Mehla et al., 2019;Saito et al.,

2014). Tau pathologies were not found in APPNL-G-F KI mice.

The mice also showed neuroinflammation and dysregulation

of β-catenin and NF-κB signaling pathways at 6 months (Liu

et al., 2021b). Using this model, studies demonstrated that

Cathepsin E could modulate microglial activation and neu-

rodegeneration, and inhibit Aβ pathology and neuroin-

flammation (Xie et al., 2022); two non-steroidal anti-

inflammatory drugs (dexketoprofen and etodolac) and two

anti-hypertensives (penbutolol and bendroflumethiazide)

could reduce Aβ plaque burden and reverse cognitive im-

pairment (Pauls et al., 2021).

3×Tg-AD mice

3×Tg-AD mice were constructed by microinjection of two

human transgenes (APP KM670/671NL mutation and MAPT

P30IL mutation, under the control of mouse Thy1.2 pro-

moter) into single-cell embryos from homozygous PS1

(M146V) KI mice (Oddo et al., 2003). The mice showed

intraneuronal Aβ deposits in the hippocampus, cortex and

amygdala, retention/retrieval deficit at 4 months (Billings et

al., 2005). The mice exhibited extracellular Aβ deposits in

Li, X., et al. Sci China Life Sci

the frontal cortex, decreased LTP, impaired basal synaptic

transmission, and learning and memory deficits in the Barnes

maze at 6 months (Billings et al., 2005;Oddo et al., 2003;

Stover et al., 2015). Gliosis appeared at 7 months of age and

increased with age (Caruso et al., 2013). Tau phosphoryla-

tion and NFTs appeared in the hippocampal CA1 neurons at

12 months, and progressed to the cortex (Oddo et al., 2003).

The mice had sexual dimorphism, as reflected by increased

cognitive deficits in females and increased levels of novelty-

induced behavioral inhibition in males (Blázquez et al.,

2014). Plasma BDNF levels in mice could predict synaptic

plasticity and memory deficits (Cocco et al., 2020). This

mouse model is usually used to study AD treatment. For

example, overexpression of phospholipid transfer protein

decreased senile plaques and NFTs, thereby improving

cognitive impairment in the mice (Wang et al., 2021c). Pa-

clitaxel delivered via the intranasal route could increase

axonal transport rates, reduce phospho-tau-containing neu-

rons, and improve performance in behavioral testing in

3×Tg-AD mice (Cross et al., 2021). Shortening theryanodine

receptor 2 open time with R-carvedilol rescued these AD-

related deficits in 3×Tg mice (Liu et al., 2021c).

5×FAD mice

5×FAD mice were constructed by co-injecting two vectors

encoding APP with KM670/671NL (Sweden), I716V

(Florida), and V717I (London) mutations and PSEN1 with

M146L and L286V mutations, each driven by the mouse

Thy1 promoter (Oakley et al., 2006). The 5×FAD model was

initially constructed with three lines, including Tg6799,

Tg7092 and Tg7031. Among them Tg6799 is the fast line for

behavioral and amyloid pathological changes, Tg7031 is the

slow line, and Tg7092 is in the middle. Tg6799 is the most

widely used line, so in this review we mainly described the

line Tg6799 (Oakley et al., 2006). The 5×FAD (B6SJL) mice

are the original 5×FAD line, on a hybrid B6SJL background.

The 5×FAD (B6SJL) mice showed intraneuronal Aβ42 ac-

cumulation at 1.5 months, extracellular amyloid deposition

and gliosis at 2 months, that increased with age, and plaques

throughout the hippocampus and cortex at 6 months (Oakley

et al., 2006). Deficits in basal synaptic transmission and LTP

of the hippocampus were observed between 4 to 6 months

(Crouzin et al., 2013;Kimura and Ohno, 2009). Synaptic

degeneration including presynaptic marker synaptophysin,

syntaxin and postsynaptic marker PSD-95 decline was ob-

served at 4 and 9 months, respectively, and neuronal loss in

cortical layer 5 and subiculum was observed at about

6 months, which progressed to other regions (Oakley et al.,

2006). Impaired spatial working memory in the MWM and

Y-maze test and impaired remote memory stabilization in a

contextual-fear-conditioning test were observed by 4 to

6 months, while impaired learning and social recognition

were observed at 9–12 months (Flanigan et al., 2014;Kimura

and Ohno, 2009;Oakley et al., 2006;Xiao et al., 2015). The

5×FAD (B6SJL)mice also showed other behavioral changes,

such as olfactory, motor, and hearing impairment at 6, 9, and

14–16 months, respectively (Flanigan et al., 2014;O’Leary

et al., 2018;O’Leary et al., 2017;Xiao et al., 2015). The

5×FAD (C57BL6) is obtained by 5×FAD (B6SJL) back-

crossing C57BL6 mice for several generations. The earliest

pathological features of 5×FAD (C57BL6) mice are in-

traneuronal Aβ accumulation and synaptic deficits in cortical

layer V neurons at 1.5–2 months (Buskila et al., 2013;Ri-

chard et al., 2015). Extracellular plaques were observed in

hippocampus, cortex, and thalamus of 2-month animals

(Richard et al., 2015). Progressive CAA on leptomeningeal

and penetrating vessels started at 3 months (Giannoni et al.,

2016). Impairment of spatial working memory in

3–6 months old 5×FAD (C57BL6) mice is later than the

5×FAD (B6SJL) mice (Jawhar et al., 2012). 40% loss of

layer V pyramidal neurons was detected in 12 months old

5×FAD (C57BL6) mice, but the total number of neurons in

hippocampus and cortex was not different from that in

wildtype mice (Jawhar et al., 2012). The 5×FAD (C57BL6)

mice also showed other behavioral changes, such as reduced

anxiety, abnormal reflexes, sensorimotor deficits, at 3, 5, and

9 months, respectively (Jawhar et al., 2012;Richard et al.,

2015). 5×FAD mouse model is widely used in AD drug

development (Keren-Shaul et al., 2017;Wang et al., 2019;

Xiao et al., 2015). For example, GV-971, approved by the

Chinese Food and Drug Administration for the treatment of

AD, was reported to harness neuroinflammation and reverse

cognition impairment in this model (Wang et al., 2019).

Salidroside protected neurite morphology, mitigated Aβ pa-

thology, and improved cognitive function in this model (Yao

et al., 2022). Exenatide reduced Aβ1-42 deposition in the

hippocampal CA1 region, alleviated synaptic degradation in

the hippocampus, and improved the learning ability and

spatial memory ability in this model (An et al., 2019). Many

drugs targeting AβO had shown therapeutic efficacy in this

model, which were described in detail in the next section.

APPPS1 mice

APPPS1 (APPPS1-21) mouse model was constructed by co-

injecting two vectors that encode mutant APP KM670/

671NL(Sweden) and PSEN1 L166P, respectively. Aβ de-

position began in the cortex at 6 weeks of age, and activated

microglia around Aβ deposits as well as increased astro-

gliosis, Aβ deposition in the hippocampus at 3–4 months of

age (Radde et al., 2006). Synaptic loss began at 4 weeks after

plaque formation and continued for several months (Bittner

et al., 2012). LTP was impaired in hippocampal CA1 region

at 8 and 15 months of age (Gengler et al., 2010). Modest

neuron loss was found in the granule cell layer of the DG and

26 Li, X., et al. Sci China Life Sci

other subregions with high neuronal density in 17-month-old

mice (Rupp et al., 2011). Spatial learning and memory were

impaired at 7 months (Serneels et al., 2009), and reversal

learning was impaired at 8 months of age (Radde et al.,

2006). This mouse model is commonly used in AD treatment

studies. Specifically, 7-day treatment of preweaned male

mice with antibiotic (ABX) is associated with reductions of

Aβ amyloidosis, plaque-localized microglia morphologies,

and Aβ-associated degenerative changes at 9 weeks of age.

Furthermore, fecal microbiota transplantation into ABX-

treated male mice completely restored the above pathologi-

cal changes (Dodiya et al., 2020;Dodiya et al., 2022). Aβ

toxicity inhibitor SEN1500 showed a positive effect on

cognition in APPPS1 mice (Lo et al., 2013). Another study

showed that prolonged treatment with the pan-histone dea-

cetylase inhibitor sodium butyrate improved associative

memory in APPPS1 mice (Govindarajan et al., 2011). A

recent study used a genetic modification strategy by injecting

virus into the median raphe nucleus of APPPS1 mice, and

found that ETV4 activation of VGLUT3 transcription could

upscale the efficacy of spatial memory retrieval, which

provided a promising therapeutic target for AD (He et al.,

2022).

APPswe/PSEN1dE9 mice

APPswe/PSEN1dE9 mice were constructed by co-injecting

two vectors that encode mutant APP and PSEN1, respec-

tively. The APP sequence contains three humanized sites

and KM670/671NL (Sweden) mutation, and the PSEN1

sequence encodes human presenilin-1 lacking exon 9

(Jankowsky et al., 2001). The mice first showed plaques,

gliosis and synapse loss at 4 months (Jackson et al., 2013;

Jankowsky et al., 2001;Malm et al., 2007;Minkeviciene et

al., 2008). Plaques emerged in cortex at 4 months, pro-

gressed to the hippocampus at 6 months, and increased in

size and number with age (Jackson et al., 2013;Minkevi-

ciene et al., 2008). There was amyloid deposition on the

cerebral arteriole wall at 7 months (Kim and Jeong, 2015).

Cognitive impairment measured by MWM was observed

between 6 and 10 months and worsened with age. Phos-

phorylated tau was observed in hippocampal CA3 neurons

at 16 months (Malm et al., 2007;Minkeviciene et al., 2008).

This mouse model is also commonly used in AD drug stu-

dies. For example, GV-971 was reported to harness neu-

roinflammation and reverse the cognitive impairment in this

model (Wang et al., 2019). Chronic oral masitinib treatment

promoted a recovery of synaptic markers, and restored

normal spatial learning performance in this model (Li et al.,

2020).

The phenotypic characteristics and applications of com-

monly used AD transgenic mouse models are described be-

low (Table 6).

AβO pathology related transgenic mouse models

and clinical translation

The earliest mouse model to report accumulation of AβO in

the brain is the Tg2576 mice, which carry 2 mutations (hu-

man APP695 containing K670N, M671L) (Chang et al.,

2003). It started to show Aβ42 oligomers in the cortex at

11 months (Takahashi et al., 2004), and gradually spread to

other regions especially hippocampus and striatum at

13 months, and reached the highest level in hippocampus

and cortex at 17 months (Chang et al., 2003). The number

and size of Aβ42 oligomer deposits increased after

20 months (Takahashi et al., 2004). Subsequently, Tg-SwDI

mice with four mutations (human APP770 containing

K670N/M671L, E693Q, D694N) (Miao et al., 2005a),

APP23 with two mutations (human APP751 containing

K670N, M671L) (Lefterov et al., 2009), J20 (Murata et al.,

2010) and McGill-Thyl-APP Tg mice (Ferretti et al., 2012;

Ferretti et al., 2011) with three mutations (human APP751

containing K670N, M671L, V717F) were reported to show

age-dependent AβO accumulation in brain neurons prior to

plaque appearance. While APP E693Δ-Tg (human APP695

containing E693Δ) (Tomiyama et al., 2010;Umeda et al.,

2011), APP Dutch (human APP751 containing E693Q)

(Gandy et al., 2010;Price et al., 2014), OSK-KI (APP

E693Δ) (Umeda et al., 2017), and PS1V97L Tg mice (Zhang

et al., 2014) that carry single mutations were reported to

show age-related AβO accumulation in cortical and hippo-

campal neurons, no extracellular Aβ deposition of any forms

was found.

The model carrying multiple gene mutations of APP,

PSEN1,PSEN2,MAPT or BACE1 also showed pathological

oligomers accumulation. In 3×Tg mice brain, AβOs in-

creased at 6 months, decreased briefly at 9–12 months, and

increased again with age at 12–20 months (Oddo et al.,

2006). AβOs appeared in the brains of 5×FAD (Tg6799)

mice at 6 months of age, and BACE1 gene deletion resulted

in the reduction of AβOs in the mice brains (Ohno et al.,

2006). Age-dependent accumulation of AβO started at

7 months in the brain of APP/PS1 mice (Bruggink et al.,

2013). PS2APP mice lacking Trem2 showed increased AβOs

in hippocampus, in addition to more diffused plaques in mice

brain (Meilandt et al., 2020).

Drug treatment is needed to prevent, delay the onset, slow

the progression, and improve the symptoms of AD (Cum-

mings et al., 2022). The large body of evidence that AβOs are

both necessary and sufficient to trigger AD-associated

memory malfunction and neurodegeneration, coupled with

the extensive literature of AβO-triggered cellular and beha-

vioral effects, sets the stage for new AD therapeutic ap-

proaches targeting AβO (Bayer, 2022;Selkoe and Hardy,

2016;Sun et al., 2021). Several drugs targeting AβO have

been tested in AβO-induced transgenic mouse models, with

Li, X., et al. Sci China Life Sci

Table 6 The main characters and applications of each line

Model name Main characters Applications

PS1(I213T) KI Elevated Aβ42 and Aβ42/40 ratio, phosphorylated tau started at young age,

tangles and spatial learning deficits appeared in middle age. No data

PS1(P117L) Impaired neurogenesis as early as 1 month; plaque and tau phosphorylation

were seen at young age. Mixed mouse models with

other genes

PS1V97L Tg AβO accumulation, glial cell activation, decreased LTP, phosphorylated tau, NFTs,

spatial learning and memory impairment occurred in young age; neuronal damage

was occasionally seen in middle age; neurodegeneration occurred in old age. Sulforaphane, honokiol

APPE693Δ-Tg AβO accumulation, hyperphosphorylated tau, decreased synaptic density started at

young age; microgliosis was observed in middle age; astrocytosis and neuron loss

occurred in old age.

Mixed mouse models with

other genes

APP23 Spatial memory impairment as early as 3 months; plaque, CAA, glial cell

activation and hyperphosphorylated tau appeared in young adult mice;

neuron loss occurred in old age.

Anti-Aβ antibodies and other drugs that

block the formation of Aβ multimers

TAS10 (Thy1-APPswe) Spatial learning and memory decline, and dystrophic neurites, lipid deposits, gliosis

started at young age; plaques and working memory deficits appeared in middle age;

synapses loss occurred in old age. No data

Tg2576 Reduced LTP, spatial and non-spatial orientation and memory deficits appeared

in young age; increased plaques, hyperphosphorylated tau and extensive CAA

were seen in old age.

Aducanumab, bexarotene, memantine,

oat extract avenanthramide-C

PDAPP (line109) Learning, working memory, recognition memory and synaptic dysfunction appeared

at <6 months, followed by plaques deformed extensively with age and glial cell

activation; phosphorylated tau and CAA were detectable in old age. 2B3, semagacestat

APP(V717I) Reduced LTP and impairment of learning and memory started at young age;

increased Aβ accumulation (including plaques and CAA) and inflammation occurred

in middle age. Mixed mouse models with other genes

JNPL3(P301L) NFTs appeared in young age, neuronal loss and astrogliosis occurred in middle age;

motor and behavioral problems by 10 months. Anti-tau antibodies

rTg(tauP301L)4510 Gliosis, tau pathology, neuron loss, synaptic dysfunction, brain weight decreased

and cognitive impairment appeared in young adults; forebrain atrophy was

seen in middle age.

Doxycycline, trazodone, epicatechin,

LDN/OSU-0215111

Tau P301S (Line PS19)

Tau hyperphosphorylation, impaired axonal transport, microgliosis, decreased

synaptophysin and motor deficits as early as 3 months; followed by increased

inflammatory factors and synaptic dysfunction in CA1, progressive NFTs and

gliosis in multiple brain regions and spinal cord; working memory, impaired

spatial learning and memory, contextual memory, sociability, and object

recognition; hippocampal atrophy and cortical atrophy occurred in middle age;

80% percent of mice died by 12 months.

Metformin, tryptophan-tyrosine-related

β-lactopeptides, ibrutinib, combined

with AD risk factors

Tg-SwDI Insoluble Aβ accumulation and cognitive deficits began at 3 months; Aβ

plaques-like deposits, CAA and gliosis increased with age at 6 months. cGMP-grade AV-1959D vaccine,

taxifolin, minocycline

J20 Increased Aβ deposits in the hippocampus began at 1 months; synaptic

dysfunction and gliosis occurred in young age.

Tumor necrosis factor receptor

2 stimulation, adult neurogenesis

modulation, mTOR attenuation

TgCRND8 Plaques, glial cell activation and cognitive impairment began at 3 months; followed

by neuronal loss, reduced LTP and decreased synaptophysin around the plaques in

young age; hyperphosphorylated tau aggregation and CAA occurred in middle age.

Nano-Honokiol, magnolol,

isorhynchophylline

APPNL-G-F KI Elevated level of Aβ42 in the cortex started at 2 months; gliosis, neurodegeneration,

synaptic dysfunction and cognitive impairment appeared in young age. Cathepsin E, dexketoprofen , etodolac,

penbutolol , bendroflumethiazide

3×Tg-AD Aβ deposits, synaptic dysfunction, gliosis, decreased LTP and cognitive impairment

occurred in young age; hyperphosphorylated tau and NFTs were seen in middle age. Paclitaxel, R-carvedilol,

butylphthalide

5×FAD (B6SJL)

Intraneuronal Aβ42 accumulation at 1.5 months; followed by extracellular amyloid

deposition and gliosis increased with age; plaques, neuron loss, synaptic dysfunction,

spatial working memory, remote memory deficits at 6 months; impaired learning,

social recognition, motor and hearing were observed in middle age. GV-971, salidroside, exenatide, 9D5,

coassembly composed of

cyclodextrin and calixarene

5×FAD (C57BL6)

Intraneuronal Aβ42 accumulation and synaptic deficits in cortical layer V neurons at

1.5-2 months; followed by extracellular amyloid deposition, CAA and gliosis

increased with age; spatial working memory deficits in young age; layer V neurons

loss in middle age.

APPPS1 Plaques, activated microglia, astrogliosis, dendritic spine loss appeared at

<3 months; impaired LTP and cognitive deficits, modest neuron loss was

found in old age.

ABX, fecal microbiota transplantation,

SEN1500, sodium butyrate, tenuifolin,

ginsenoside, cryptotanshinone, carnosic

acid, butylphthalide, lycium barbarum

extract, genetic modification strategy by

virus injection

APPswe/PSEN1dE9 Plaques, gliosis and synapse loss began at 4 months; followed by CAA and cognitive

impairment; phosphorylated tau was observed in middle age. GV-971, masitinib

28 Li, X., et al. Sci China Life Sci

strategies including directly clearing AβOs, blocking AβO

surface receptors, interfering with AβO-induced signaling

pathways, or decreasing downstream effectors such as tau

(Overk and Masliah, 2014). Selective AβO antibodies pre-

vent AD-like pathology and rescue memory performance

(Klyubin et al., 2005;Lambert et al., 2007;Sebollela et al.,

2017). Several drugs have shown therapeutic effects, such as

aducanumab that binds to both soluble AβOs and insoluble

fibrils in Tg2576 mice (Gamage and Kumar, 2017). The

murine version of humanized antibody BAN2401 (mAb158)

exhibited a strong binding preference for soluble AβOs and

protofibrils over Aβ monomers in tg-ArcSwe mice (Tucker

et al., 2015). Gantenerumab and crenezumab were also found

binding to AβOs in the PS2APP mouse model (Barrow et al.,

2017;Meilandt et al., 2019). Passive immunization of

5×FAD mice with the monoclonal antibody 9D5, which re-

acted with low molecular weight AβOs, reduced plaques and

rescued behavioral deficits (Wirths et al., 2010). The

monoclonal antibody 07/01 prevented in vitro toxicity of

AβOs and normalized in vivo behavioral deficits in AD

mouse model (Frost et al., 2015). A coassembly composed of

cyclodextrin (CD) and calixarene (CA) was able to eliminate

amyloid plaques, and degrade Aβ1-42 monomers and oli-

gomers in 5×FAD mice (Wang et al., 2021a).

In addition to the above antibody drugs, a variety of drugs

especially traditional Chinese medicine monomers were ef-

fective in AβO based mouse models (Chen et al., 2020), and

had multi-target anti-dementia components (Jia et al., 2020c;

Li et al., 2021a). More recently, sulforaphane was found to

improve spatial cognition in PS1V97L Tg mice and improve

memory impairment and depressive-like behavior in rats

with intracerebroventricular injection AβOs, with potential

mechanism of anti-AβOs, anti-tau, anti-oxidative stress and

anti-neuroinflammation, and protecting serotonergic system

(Hou et al., 2018;Wang et al., 2020). Honokiol was found

effective in PS1V97L Tg mice, with a potential mechanism

of up-regulating peroxisome proliferator-activated receptor γ

and peroxisome proliferator-activated receptor-γ coactivator-

1α through SIRT3 pathway, thus improving mitochondrial

function and apoptosis, and promoting microglial phagocytic

function (Li et al., 2018;Li et al., 2021b). Tenuifolin (Zhang

et al., 2008), ginsenoside (Li et al., 2016), cryptotanshinone

(Mei et al., 2009) and carnosic acid (Yi-Bin et al., 2022) were

found effective in APP/PS1 mice, with potential mechanisms

of anti-neuroinflammation and anti-oxidative stress through

Nrf2/NF-κB and CEBPβ-NFκB signaling pathways, redu-

cing tau phosphorylation, synaptoprotection and mitopro-

tection via PI3K/Akt/GSK3β pathway and regulating

NMDAR2B downstream cascades (Chen and Jia, 2020;

Chen et al., 2022;Jiao and Jia, 2022;Liu et al., 2023;Lyu

and Jia, 2022). In addition, butylphthalide and lycium bar-

barum extract were found effective in 3×Tg and/or APP/PS1

mice, with potential mechanisms of reducing tau phosphor-

ylation, reducing AβO-induced inflammatory reactions, sy-

napse stabilization, anti-oxidation and anti-apoptosis through

CaMKⅡα pathway (Li et al., 2022;Liu et al., 2021a;Peng et

al., 2010;Sun et al., 2022;Zhang et al., 2016).

Among the drugs that showed therapeutic efficacy in AβO

based mouse models, several drugs have shown efficacy in

clinical trials or have biomarker data, including two anti-

bodies that engage AβOs, aducanumab and lecanemab (Se-

vigny et al., 2016;Swanson et al., 2021;van Dyck et al.,

2023). Butylphthalide, in combination with donepezil, was

found effective in delaying cognitive decline in patients with

mild to moderate AD (Wang et al., 2021b). Sulforaphane has

entered clinical trials for AD population (NCT04213391).

Advantages and limitations of transgenic mouse

models

Transgenic mouse models are useful tools for studying early

AD pathology as well as the spatial and temporal features of

each pathology, which would be helpful for developing early

diagnostic markers for AD even before symptoms appear

(behavioral changes in mice), namely Aβ, tau, neuronal da-

mage, microglia activation, and synaptic changes as shown

in the tables. The mouse models are also useful in in-

vestigating the upstream and downstream mechanisms and

molecular pathways of each mechanism, which would be

helpful for developing target treatments. Having that said,

the heterogeneity and variation of each transgenic mouse

model in terms of phenotypes make it inconclusive about AD

pathogenesis, which requires further verification in higher

order animals (namely non-human primates) and/or clinical

studies.

Single transgenic mouse models

Single-transgenic mouse models have the following ad-

vantages and limitations. First, the behavioral changes ap-

pear relatively late, not as early as multi-transgenic models

such as 5×FAD model, thus the duration for drug experi-

ments might be longer, which is not efficient for drug

screening. However, it is more consistent with real world

situation and thus is more suitable for translational research

of promising drugs with known targets of action that match

the pathogenic features of the mouse models. There is evi-

dence showing that the chance of translation of findings in

transgenic mouse models to humans decreases as the focus

shifts from the targets of interest to behavioral or other

biomarker end points (Scearce-Levie et al., 2020). Second,

many single-transgenic mouse models only mimic a few

pathogenic characters of AD, thus cannot reflect the features

of the whole AD population. In this regard, models with

more pathogenic features such as PS1V97L Tg mice might

Li, X., et al. Sci China Life Sci

be a good choice. Third, many single-transgenic mouse

models are developed locally, and not widely used or fully

studied for their pathogenic features or mechanisms, and not

verified by other labs. In the future, more efforts are needed

for cross-validation.

Multi-transgenic mouse models

Multi-transgenic mouse models have the following ad-

vantages and limitations. It was found that models expressing

multiple FAD gene mutations could lead to earlier and more

severe pathology (Drummond and Wisniewski, 2017). In-

creased number of APP mutations or superimposed with

PSEN1 or PSEN2 mutations can lead to earlier AD-related

pathology (Irizarry et al., 1997;Jankowsky et al., 2004;

Mehla et al., 2019;Nilsson et al., 2014;Oakley et al., 2006;

Richards et al., 2003;Sato et al., 2021), and shorten the

experimental period. The 3×Tg mice constructed in combi-

nation with APP,PSEN1, and MAPT gene mutations can

simulate plaque and NFTs, the two typical AD pathological

manifestations (Oddo et al., 2003), but it is debatable whether

this combination can represent AD (King, 2018). In addition,

crossbreeding 5×FAD mice with risk gene mice such as

BACE,APOE, and TREM2, can illustrate the interaction of

these risk genes with pathogenic gene mutations during the

onset and development of AD (Hu et al., 2018;Song et al.,

2018;Youmans et al., 2012). Although studies in these mouse

models have made important contributions in explaining the

pathologic changes of AD, drug efficacy provided by these

models has seldom been translated into clinical practice

(Josephine Boder and Banerjee, 2021;Zhang et al., 2020).

First, the genetic background of such models is rarely seen in

human genetic characteristics (Martini et al., 2018). FAD

patients usually carry only one pathogenic variant, and more

than 80% of FAD patients are not found to carry the reported

pathogenic variant (Jia et al., 2020b). Whether mechanisms

and potentially effective drugs obtained from multi-trans-

genic animals can be completely translated into AD patients

with a single mutation or without these mutations still re-

quires more validation and interpretation (King, 2018;

Mckean et al., 2021). Second, the additive effect of multiple

gene mutations in the multi-transgenic model has shortened

the process of AD, that are not in line with the chronic pro-

gression feature especially in preclinical stage of AD before

symptoms onset. As a result, it is difficult to study the

treatment strategy in terms of timing and duration. Third, the

phenotype changes are likely to be faster and more severe

than in single-transgenic mouse models, thus it is difficult for

prevention study as well as risk factor managements. Pre-

vention trials take the longest duration, even longer than

disease-modifying therapy (Cummings et al., 2022). Results

of positive effects in young models cannot be verified in

elderly AD patients (King, 2018).

Tg mice vs. KI mice

Tg is to integrate foreign genes into mouse chromosomes at

random to obtain randomly inserted transgenic mice (Jae-

nisch and Mintz, 1974;Oakley et al., 2006). Because the

target gene is randomly integrated into the genome, the ex-

pression of the target gene is affected by the integrated lo-

cation, and the expression may be high or low, or even not

expressed (Garrick et al., 1998). This feature has two sides.

The advantage is that researchers can select the mice with the

best expression level from mice with various expression le-

vels for scientific research. However, different expression

strains need to be established in the early stage, so the time

and labor costs are high. At the same time, due to random

integration, other gene sequences of mice may be destroyed

to obtain phenotypes unrelated to the target gene. Further-

more, Tg mice have suffered from artificial phenotypes

caused by overproduction or mislocalization, as well as

calpastatin deficiency-induced early lethality, calpain acti-

vation, neuronal cell death without tau pathology, en-

doplasmic reticulum stresses, and inflammasome

involvement. Such artifacts generate more uncertainties in

the interpretation of experimental results (Sasaguri et al.,

2022). KI is a gene-targeting technology that inserts the

target gene segment into a pre-selected site at a fixed point,

usually the Rosa26 locus (Friedrich and Soriano, 1991;

Soriano, 1999). Inserting the target gene at this site does not

affect the expression of endogenous genes in mice. The

mouse model constructed by this method has only one strain,

and the expression amount is controllable, but the over-

expression model cannot be obtained at one time.

Intraneuronal Aβ/APP vs. extracellular plaque

deposition

Zou et al. (2015) reported that the accumulation APP but not

Aβ in neurons was observed in 4–5 months old APP23 mice,

and the intraneuronal APP content was inversely correlated

with the absolute spine density and the relative number of

mushroom spines. This elucidates that APP accumulation

can lead to the decline of dendritic spines and cognitive

impairment, which is different from the mechanism of AD

caused by Aβ accumulation, suggesting that APP accumu-

lation in neurons should be paid attention to in the over-

expressed APP mouse models. Extracellular plaque

deposition has been considered as the major neuropatholo-

gical marker of AD, those mouse models showing only

plaque deposition provide strong evidence for understanding

plaque formation and the effect of plaque on other AD fea-

tures (Sanchez-Varo et al., 2022). Furthermore, no matter the

pathological features in these AD mouse models were in-

traneuronal Aβ pathology or extracellular plaque deposition,

they were accompanied by other pathological changes or

30 Li, X., et al. Sci China Life Sci

cognitive impairment, but the time of occurrence was dif-

ferent. From the perspective of drug research on AD, multi-

target therapy and asymptomatic phase intervention are the

current hotspot and key (Cheong et al., 2022;Crous-Bou et

al., 2017). Intraneuronal Aβ accumulation is an early event

of plaque formation. Intervention at the stage of Aβ accu-

mulation may provide more evidence for AD prevention and

treatment. Some mouse models showing intraneuronal Aβ

pathology without plaque formation also have other AD-

related pathological/behavioral changes, such as PS1V97L

Tg (Zhang et al., 2014) and APP E693Δ-Tg (Tomiyama et

al., 2010). In addition, much evidence indicates that simply

removing amyloid plaques may not significantly affect AD

progression, many drugs that are based on Aβ targets aim to

reduce Aβ production or accumulation (Karran and De

Strooper, 2022). As a result, these models can be used as

preclinical AD models for ultra-early intervention studies

(Sasaguri et al., 2017) and to study the effects of Aβ accu-

mulation on neurons, glial cells, synaptic morphology and

function, mitochondria, oxidative stress and neuroin-

flammation (Sehar et al., 2022), that are conducive to the

discovery of other pathways and therapeutic targets affecting

the pathogenesis of AD.

Inconsistency between transgenic mouse models and

clinical trials in drug development

In animal models, which are mechanistically simpler by

design, only a small subset of the molecules that may con-

tribute to disease are likely to be impacted, whereas other

aspects of human disease are not accurately reflected. There

is seldom a good model which reproduces all features of AD.

It is still unknown to what extent cellular phenotypes induced

in these models mimic human situation. Sixty-five million

years of evolutionary divergence cannot be ignored

(Sierksma et al., 2020). Due to overexpression artifacts,

unwanted genetic alterations, lengthy experiments and/or

ethical approval and considerations, drugs that show good

efficacy and safety in transgenic mouse models are often

failed to enter clinical trials (Sierksma et al., 2020). Targeted

drugs, either enhancers or suppressors, can exert their effects

on the expression of genes that are remote from their location

(Nott et al., 2019). Many enhancers affected by causal var-

iants are highly specific to brain region, cell type or state

(Huang et al., 2017;Nott et al., 2019). Many enhancer re-

gions rather than promoter regions, often myeloid and mi-

croglial, are significantly enriched for AD-associated

variants (Gjoneska et al., 2015;Nott et al., 2019). Further-

more, the genomic variants captured from different AD pa-

tients are different, but the pathological phenotypes of AD

patients are similar (Sierksma et al., 2020). In contrast, in

transgenic mouse models, different genomic variants lead to

various pathological phenotypes. Such inconsistency makes

it difficult to specify how AD-associated variants may exert

their effects on pathological phenotypes. As a result, there is

a huge gap between pathological phenotypes and genetic

phenotypes, which further contributes to the inconsistency

between drug development in transgenic models and clinical

trials.

In addition to the Aβ pathological phenotypes that were

present in AD, in clinical field, symptoms usually start to

show up along with the occurrence of tau pathology. In-

creasing evidence has demonstrated a strong correlation

between tau pathology and neurodegeneration and memory

impairment, indicating an essential role of pathological tau in

driving AD symptoms (Long and Holtzman, 2019;Veitch et

al., 2019). Mouse models that show tau pathology might be

indicative of symptom onset as well as disease progression,

which might be translated into clinical trials as outcome

measures of disease progression. The limitations, however,

are that tau pathology usually appears after amyloid pa-

thology, thus transgenic mouse models showing only tau

pathology were probably not suitable for early detection of

disease in preclinical or prodromal phase. In addition to Aβ

pathology and tau pathology, neurodegeneration (e.g., brain

atrophy) is another important pathologic feature for AD

patients, however, it is not developed in the amyloid mouse

models with known pathogenic gene mutation (regardless of

single or multi-transgenic), but developed in most MAPT

single-transgenic mouse models. A possible reason is that

neurodegeneration is a downstream effect, and more related

to tau pathology and disease progression, while amyloid

pathology usually occurs earlier and is probably an upstream

mechanism that acts together with many other pathogenic

pathways to finally lead to neurodegeneration. As a result,

these mouse models are limited in testing downstream ef-

fects.

Although this review mainly focuses on AD transgenic

mouse models, which are the most widely used ones at

present, there are other AD models that have some ad-

vantages over mouse models in some way. Drosophila and

C.elegans are also often used animal models for AD

(Prüßing et al., 2013;van Ham et al., 2009). Although they

are somewhat deficient in cognitive function assessment

compared to rodents, both are model animals with simple

genetic manipulation, which can easily construct transgenic

models of single or double copies of Aβ42 expressed by

whole neurons or motor neurons in the central nervous sys-

tem, thus are suitable as preliminary screening models for

new drugs of AD treatment. At present, the lag of experi-

mental model animal research and the failure to fully cover

and replicate various pathologies and phenotypes of AD are

the bottlenecks restricting the research on AD mechanism

and drug development. Recently, Pang et al. constructed a

transgenic rat model that carries three human-derived APP

gene mutations AppNL-G-F, and the study showed that the rat

Li, X., et al. Sci China Life Sci

model presented more similar pathology and disease pro-

gression to human AD patients than other existing AD ani-

mal models (Pang et al., 2022), which suggests that rat model

might be of great significance in studying the pathological

development and mechanism of AD in the future, and may

also be more suitable for the development and verification of

some potential anti-AD drugs. Non-human primates and

human beings are similar in brain anatomy, neuropathy

characteristics and biological behavior patterns, especially

rhesus monkeys. In the brains of rhesus monkeys, observed

Aβ deposition containing senile plaques and neurofibrillary

tangled phenomenon, whether spontaneous or induced

models, can better replicate AD-related pathological and

physiological characteristics, but expensive costs and scarce

resources limit the large number of applications of non-hu-

man primates (Capitanio and Emborg, 2008).

APP-based transgenic models were successful in predict-

ing molecular pathways that could impact amyloid accu-

mulation in the clinic, but had less value in predicting the

specific properties of anti-Aβ therapies that were most likely

to reduce plaque load in patients, and had not yet translated

into robust effects on cognition in well-powered clinical

trials (Scearce-Levie et al., 2020). Such discrepancy may be

due to: the specific APP-based model, end points used in

preclinical studies, the limitations inherent in clinical trials,

and uncertainty about the specific form of Aβ that drives

pathology (Karran and Hardy, 2014). In addition, Aβ pa-

thology may not be the direct cause of neurodegeneration

and cognitive deficits. It is very likely that the very few Aβ

antibody-based clinical trials reported to show some effects

in the early stage of AD take effects by reducing Aβ pa-

thology-induced downstream detrimental events such as tau

pathology and neuroinflammation, that serve as the real

driver of neurodegenerative and cognitive impairment. As a

result, APP-based transgenic models might be useful in

testing anti-Aβ therapies at the early stage of disease, while

multi-target therapeutic strategies might be more suitable for

later stage treatment. The probability of translation of pre-

clinical findings to the clinic depends on both the type of

model and the end points selected. The chance of translating

to human decreases as the focus shifts from end points of the

actual target to end points such as cognitive behaviors or

brain atrophy (Scearce-Levie et al., 2020). Scientists have

proposed a framework that is centered on the use of animal

models to explore disease-relevant biology proximal to the

target of interest, and to identify candidate biomarkers with

potential clinical translatability (Scearce-Levie et al., 2020).

Bridging the gap would be critical and helpful for stratifi-

cation of patients for clinical trials, and personalized medi-

cine based on genetic profile.

Furthermore, in clinical practice, the phenomenon of fa-

milial co-segregation is very strong, however, in animal

models, we sometimes fail to get positive results to verify the

genetic phenomenon. Possible reasons are: (i) there might be

other synergistic gene(s) in the family, which was not con-

structed into the mouse model; (ii) there might be a lack of

corresponding intermediate link or pathway for the patho-

genic gene mutation to play the same role in the mouse

model, which could lead to the limited pathogenic effects of

the gene; (iii) the pathogenesis of AD is complex, which is

affected by various factors including genetic and environ-

mental factors, as well as lifestyles, and these factors are

difficult if not impossible to mimic or model in mice, which

may affect the results.

Conclusion and future perspectives

Transgenic mouse models have development prospects,

which can explain the different mechanisms of different

mutations and can be used for a wider range of studies. First,

they can be used for studying gene specific mechanism,

targeted drug development and gene therapy. Besides the

known pathogenic genes, more and more gene mutation sites

of the three known pathogenic genes, as well as unknown

mutations, have been found in FAD, and subsequent devel-

opment of corresponding mouse models is on the way.

Second, they can be used to study drugs with multi-target

potential efficacy. There have been studies of multi-target

drugs in the early stage of transgenic mouse models, namely

various Chinese medicine monomers, and some have entered

clinical trials. Such preclinical findings of multi-target

therapy need to be further verified or reproduced in-

dependently in other models and labs. Third, they can be

used to combine with risk factor models so as to study the

interaction of genes and risk factors, which provides a basis

for developing prevention strategies. In large-scale popula-

tion studies, a variety of risk factors for AD have been found,

namely diabetes, cerebrovascular diseases, depression, an-

xiety, malaise and fatigue, high cholesterol level and ab-

normal weight loss (Gauthier et al., 2012;Jia et al., 2020a;

Nedelec et al., 2022;Yu et al., 2020). More and more evi-

dence suggests that future AD treatment should develop to-

wards multi targets and combination therapy (Delrieu et al.,

2022), and pay more attention to the diversity and hetero-

geneity of the population (Peroutka, 2022), as well as gene-

environment interaction (Migliore and Coppedè, 2022), so as

to better reflect the real world situation.

Among the various AD transgenic models, special atten-

tion should be paid to AβO related models due to their pa-

thogenic features and promising translational advantages.

Future studies in investigating the trajectories of AβO related

pathologic changes, extended upstream and downstream

mechanisms and pathways are needed to optimize treatment

and prevention strategy. In addition, AD-related biomarkers

and behavioral phenotypes shared by models and humans

32 Li, X., et al. Sci China Life Sci

should be developed for better translation from models to

clinical trials.

Compliance and ethics The author(s) declare that they have no conflict

of interest.

Acknowledgements This work was supported by the National Natural

Science Foundation of China (U20A20354, 81530036), Beijing Brain In-

itiative from Beijing Municipal Science & Technology Commission

(Z201100005520016, Z201100005520017), the National Major R&D Pro-

jects of China-Scientific Technological Innovation 2030 (2021ZD0201802),

the National Key Scientific Instrument and Equipment Development Project

(31627803), Youth Program of National Natural Science Foundation of

China (81801048, 82101503) and Youth Elite Scientists Sponsorship Pro-

gram by CAST (YESS20200155). We would like to thank Shuya Nie, Fangyu

Li, Bingqiu Li and Wenying Liu for literature search for the clinical trans-

lation related sections.

References

Adalbert, R., Nogradi, A., Babetto, E., Janeckova, L., Walker, S.A.,

Kerschensteiner, M., Misgeld, T., and Coleman, M.P. (2009). Severely

dystrophic axons at amyloid plaques remain continuous and connected

to viable cell bodies. Brain 132, 402–416.

Alexander, A.G., Marfil, V., and Li, C. (2014). Use of Caenorhabditis

elegans as a model to study Alzheimer’s disease and other

neurodegenerative diseases. Front Genet 5, 279.

Almkvist, O., Rodriguez-Vieitez, E., Thordardottir, S., Nordberg, A.,

Viitanen, M., Lannfelt, L., and Graff, C. (2019). Longitudinal cognitive

decline in autosomal-dominant Alzheimer’s disease varies with

mutations in APP and PSEN1 genes. Neurobiol Aging 82, 40–47.

An, J., Zhou, Y., Zhang, M., Xie, Y., Ke, S., Liu, L., Pan, X., and Chen, Z.

(2019). Exenatide alleviates mitochondrial dysfunction and cognitive

impairment in the 5×FAD mouse model of Alzheimer’s disease. Behav

Brain Res 370, 111932.

Ano, Y., Takaichi, Y., Ohya, R., Uchida, K., Nakayama, H., and Takashima,

A. (2023). Tryptophan-tyrosine dipeptide improves tau-related

symptoms in tauopathy mice. Nutr Neurosci 26, 766–777.

Arancio, O., Zhang, H.P., Chen, X., Lin, C., Trinchese, F., Puzzo, D., Liu,

S., Hegde, A., Yan, S.F., Stern, A., et al. (2004). RAGE potentiates Aβ-

induced perturbation of neuronal function in transgenic mice. EMBO J

23, 4096–4105.

Arendash, G.W., King, D.L., Gordon, M.N., Morgan, D., Hatcher, J.M.,

Hope, C.E., and Diamond, D.M. (2001). Progressive, age-related

behavioral impairments in transgenic mice carrying both mutant

amyloid precursor protein and presenilin-1 transgenes. Brain Res 891,

42–53.

Armbrust, F., Bickenbach, K., Marengo, L., Pietrzik, C., and Becker-Pauly,

C. (2022). The Swedish dilemma—the almost exclusive use of

APPswe-based mouse models impedes adequate evaluation of

alternative β-secretases. Biochim Biophys Acta 1869, 119164.

Baglietto-Vargas, D., Forner, S., Cai, L., Martini, A.C., Trujillo-Estrada, L.,

Swarup, V., Nguyen, M.M.T., Do Huynh, K., Javonillo, D.I., Tran, K.

M., et al. (2021). Generation of a humanized Aβ expressing mouse

demonstrating aspects of Alzheimer’s disease-like pathology. Nat

Commun 12, 2421.

Barrow, P., Villabruna, L., Hoberman, A., Bohrmann, B., Richter, W.F., and

Schubert, C. (2017). Reproductive and developmental toxicology

studies with gantenerumab in PS2APP transgenic mice. Reprod

Toxicol 73, 362–371.

Barrow, P.A., Empson, R.M., Gladwell, S.J., Anderson, C.M., Killick, R.,

Yu, X., Jefferys, J.G.R., and Duff, K. (2000). Functional phenotype in

transgenic mice expressing mutant human presenilin-1. Neurobiol Dis

7, 119–126.

Bayer, T.A. (2022). Pyroglutamate Aβ cascade as drug target in

Alzheimer’s disease. Mol Psychiatry 27, 1880–1885.

Begley, J.G., Duan, W., Chan, S., Duff, K., and Mattson, M.P. (1999).

Altered calcium homeostasis and mitochondrial dysfunction in cortical

synaptic compartments of presenilin-1 mutant mice. J Neurochem 72,

1030–1039.

Bellucci, A., Rosi, M.C., Grossi, C., Fiorentini, A., Luccarini, I., and

Casamenti, F. (2007). Abnormal processing of tau in the brain of aged

TgCRND8 mice. Neurobiol Dis 27, 328–338.

Bellucci, A., Westwood, A.J., Ingram, E., Casamenti, F., Goedert, M., and

Spillantini, M.G. (2004). Induction of inflammatory mediators and

microglial activation in mice transgenic for mutant human P301S tau

protein. Am J Pathol 165, 1643–1652.

Billings, L.M., Oddo, S., Green, K.N., McGaugh, J.L., and LaFerla, F.M.

(2005). Intraneuronal Aβ causes the onset of early Alzheimer’s disease-

related cognitive deficits in transgenic mice. Neuron 45, 675–688.

Bittner, T., Burgold, S., Dorostkar, M.M., Fuhrmann, M., Wegenast-Braun,

B.M., Schmidt, B., Kretzschmar, H., and Herms, J. (2012). Amyloid

plaque formation precedes dendritic spine loss. Acta Neuropathol 124,

797–807.

Blázquez, G., Cañete, T., Tobeña, A., Giménez-Llort, L., and Fernández-

Teruel, A. (2014). Cognitive and emotional profiles of aged

Alzheimer’s disease (3×TgAD) mice: Effects of environmental

enrichment and sexual dimorphism. Behav Brain Res 268, 185–201.

Boekhoorn, K., Terwel, D., Biemans, B., Borghgraef, P., Wiegert, O.,

Ramakers, G.J.A., de Vos, K., Krugers, H., Tomiyama, T., Mori, H., et

al. (2006). Improved long-term potentiation and memory in young tau-

P301L transgenic mice before onset of hyperphosphorylation and

tauopathy. J Neurosci 26, 3514–3523.

Boncristiano, S., Calhoun, M.E., Howard, V., Bondolfi, L., Kaeser, S.A.,

Wiederhold, K.H., Staufenbiel, M., and Jucker, M. (2005). Neocortical

synaptic bouton number is maintained despite robust amyloid

deposition in APP23 transgenic mice. Neurobiol Aging 26, 607–613.

Borchelt, D.R., Ratovitski, T., van Lare, J., Lee, M.K., Gonzales, V.,

Jenkins, N.A., Copeland, N.G., Price, D.L., and Sisodia, S.S. (1997).

Accelerated amyloid deposition in the brains of transgenic mice

coexpressing mutant presenilin 1 and amyloid precursor proteins.

Neuron 19, 939–945.

Borchelt, D.R., Thinakaran, G., Eckman, C.B., Lee, M.K., Davenport, F.,

Ratovitsky, T., Prada, C.M., Kim, G., Seekins, S., Yager, D., et al.

(1996). Familial Alzheimer’s disease-linked presenilin 1 variants

elevate Aβ1–42/1–40 ratio in vitro and in vivo.Neuron 17, 1005–1013.

Bouter, Y., Dietrich, K., Wittnam, J.L., Rezaei-Ghaleh, N., Pillot, T., Papot-

Couturier, S., Lefebvre, T., Sprenger, F., Wirths, O., Zweckstetter, M., et

al. (2013). N-truncated amyloid β (Aβ) 4-42 forms stable aggregates

and induces acute and long-lasting behavioral deficits. Acta

Neuropathol 126, 189–205.

Brautigam, H., Steele, J.W., Westaway, D., Fraser, P.E., George-Hyslop, P.

H.S., Gandy, S., Hof, P.R., and Dickstein, D.L. (2012). The isotropic

fractionator provides evidence for differential loss of hippocampal

neurons in two mouse models of Alzheimer’s disease. Mol

Neurodegener 7, 58.

Breyhan, H., Wirths, O., Duan, K., Marcello, A., Rettig, J., and Bayer, T.A.

(2009). APP/PS1KI bigenic mice develop early synaptic deficits and

hippocampus atrophy. Acta Neuropathol 117, 677–685.

Brown, J.T., Richardson, J.C., Collingridge, G.L., Randall, A.D., and

Davies, C.H. (2005). Synaptic transmission and synchronous activity is

disrupted in hippocampal slices taken from aged TAS10 mice.

Hippocampus 15, 110–117.

Bruggink, K.A., Jongbloed, W., Biemans, E.A.L.M., Veerhuis, R.,

Claassen, J.A.H.R., Kuiperij, H.B., and Verbeek, M.M. (2013).

Amyloid-β oligomer detection by ELISA in cerebrospinal fluid and

brain tissue. Anal Biochem 433, 112–120.

Buskila, Y., Crowe, S.E., and Ellis-Davies, G.C.R. (2013). Synaptic deficits

in layer 5 neurons precede overt structural decay in 5xFAD mice.

Neuroscience 254, 152–159.

Cacciottolo, M., Morgan, T.E., and Finch, C.E. (2021). Age, sex, and

Li, X., et al. Sci China Life Sci

cerebral microbleeds in EFAD Alzheimer disease mice. Neurobiol

Aging 103, 42–51.

Calhoun, M.E., Wiederhold, K.H., Abramowski, D., Phinney, A.L., Probst,

A., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., and Jucker, M.

(1998). Neuron loss in APP transgenic mice. Nature 395, 755–756.

Capitanio, J.P., and Emborg, M.E. (2008). Contributions of non-human

primates to neuroscience research. Lancet 371, 1126–1135.

Caruso, D., Barron, A.M., Brown, M.A., Abbiati, F., Carrero, P., Pike, C.J.,

Garcia-Segura, L.M., and Melcangi, R.C. (2013). Age-related changes

in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging 34,

1080–1089.

Casas, C., Sergeant, N., Itier, J.M., Blanchard, V., Wirths, O., van der Kolk,

N., Vingtdeux, V., van de Steeg, E., Ret, G., Canton, T., et al. (2004).

Massive CA1/2 neuronal loss with intraneuronal and N-terminal

truncated Aβ42 accumulation in a novel Alzheimer transgenic model.

Am J Pathol 165, 1289–1300.

Chang, L., Bakhos, L., Wang, Z., Venton, D.L., and Klein, W.L. (2003).

Femtomole immunodetection of synthetic and endogenous amyloid-β

oligomers and its application to Alzheimer’s Disease drug candidate

screening. J Mol Neurosci 20, 305–314.

Chapman, P.F., White, G.L., Jones, M.W., Cooper-Blacketer, D., Marshall,

V.J., Irizarry, M., Younkin, L., Good, M.A., Bliss, T.V.P., Hyman, B.T.,

et al. (1999). Impaired synaptic plasticity and learning in aged amyloid

precursor protein transgenic mice. Nat Neurosci 2, 271–276.

Chen, S., and Jia, J. (2020). Tenuifolin attenuates amyloid-β42-induced

neuroinflammation in microglia through the NF-κB signaling pathway.

J Alzheimer Dis 76, 195–205.

Chen, S.Y., Gao, Y., Sun, J.Y., Meng, X.L., Yang, D., Fan, L.H., Xiang, L.,

and Wang, P. (2020). Traditional Chinese medicine: role in reducing β-

amyloid, apoptosis, autophagy, neuroinflammation, oxidative stress,

and mitochondrial dysfunction of Alzheimer’s disease. Front Pharmacol

11, 497.

Chen, Y., Wang, Y., Qin, Q., Zhang, Y., Xie, L., Xiao, J., Cao, Y., Su, Z.,

and Chen, Y. (2022). Carnosic acid ameliorated Aβ-mediated (amyloid-

β peptide) toxicity, cholinergic dysfunction and mitochondrial defect in

Caenorhabditis elegans of Alzheimer’s Model. Food Funct 13, 4624–

4640.

Cheng-Hathaway, P.J., Reed-Geaghan, E.G., Jay, T.R., Casali, B.T.,

Bemiller, S.M., Puntambekar, S.S., von Saucken, V.E., Williams, R.

Y., Karlo, J.C., Moutinho, M., et al. (2018). The Trem2 R47H variant

confers loss-of-function-like phenotypes in Alzheimer’s disease. Mol

Neurodegener 13, 29.

Cheng, I.H., Palop, J.J., Esposito, L.A., Bien-Ly, N., Yan, F., and Mucke, L.

(2004). Aggressive amyloidosis in mice expressing human amyloid

peptides with the Arctic mutation. Nat Med 10, 1190–1192.

Cheng, I.H., Scearce-Levie, K., Legleiter, J., Palop, J.J., Gerstein, H., Bien-

Ly, N., Puolivaöli, J., Lesné, S., Ashe, K.H., Muchowski, P.J., et al.

(2007). Accelerating amyloid-β fibrillization reduces oligomer levels

and functional deficits in Alzheimer disease mouse models. J Biol

Chem 282, 23818–23828.

Cheong, S.L., Tiew, J.K., Fong, Y.H., Leong, H.W., Chan, Y.M., Chan, Z.

L., and Kong, E.W.J. (2022). Current pharmacotherapy and multi-target

approaches for Alzheimer’s disease. Pharmaceuticals 15, 1560.

Chishti, M.A., Yang, D.S., Janus, C., Phinney, A.L., Horne, P., Pearson, J.,

Strome, R., Zuker, N., Loukides, J., French, J., et al. (2001). Early-onset

amyloid deposition and cognitive deficits in transgenic mice expressing

a double mutant form of amyloid precursor protein 695. J Biol Chem

276, 21562–21570.

Cocco, S., Rinaudo, M., Fusco, S., Longo, V., Gironi, K., Renna, P., Aceto,

G., Mastrodonato, A., Li Puma, D.D., Podda, M.V., et al. (2020).

Plasma BDNF levels following transcranial direct current stimulation

allow prediction of synaptic plasticity and memory deficits in 3×Tg-AD

mice. Front Cell Dev Biol 8, 541.

Codita, A., Gumucio, A., Lannfelt, L., Gellerfors, P., Winblad, B.,

Mohammed, A.H., and Nilsson, L.N.G. (2010). Impaired behavior of

female tg-ArcSwe APP mice in the IntelliCage: A longitudinal study.

Behav Brain Res 215, 83–94.

Cohen, R.M., Rezai-Zadeh, K., Weitz, T.M., Rentsendorj, A., Gate, D.,

Spivak, I., Bholat, Y., Vasilevko, V., Glabe, C.G., Breunig, J.J., et al.

(2013). A transgenic Alzheimer rat with plaques, tau pathology,

behavioral impairment, oligomeric Aβ, and frank neuronal loss. J

Neurosci 33, 6245–6256.

Colton, C.A., Wilcock, D.M., Wink, D.A., Davis, J., Van Nostrand, W.E.,

and Vitek, M.P. (2008). The effects of NOS2 gene deletion on mice

expressing mutated human AbetaPP. J Alzheimers Dis 15, 571–587.

Congdon, E.E., Pan, R., Jiang, Y., Sandusky-Beltran, L.A., Dodge, A., Lin,

Y., Liu, M., Kuo, M.H., Kong, X.P., and Sigurdsson, E.M. (2022).

Single domain antibodies targeting pathological tau protein: Influence

of four IgG subclasses on efficacy and toxicity. Ebiomedicine 84,

104249.

Cook, C., Dunmore, J.H., Murray, M.E., Scheffel, K., Shukoor, N., Tong,

J., Castanedes-Casey, M., Phillips, V., Rousseau, L., Penuliar, M.S., et

al. (2014). Severe amygdala dysfunction in a MAPT transgenic mouse

model of frontotemporal dementia. Neurobiol Aging 35, 1769–1777.

Coppola, G., Chinnathambi, S., Lee, J.J.Y., Dombroski, B.A., Baker, M.C.,

Soto-Ortolaza, A.I., Lee, S.E., Klein, E., Huang, A.Y., Sears, R., et al.

(2012). Evidence for a role of the rare p.A152T variant in MAPT in

increasing the risk for FTD-spectrum and Alzheimer’s diseases. Hum

Mol Genet 21, 3500–3512.

Cramer, P.E., Cirrito, J.R., Wesson, D.W., Lee, C.Y.D., Karlo, J.C., Zinn, A.

E., Casali, B.T., Restivo, J.L., Goebel, W.D., James, M.J., et al. (2012).

ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits

in AD mouse models. Science 335, 1503–1506.

Cross, D.J., Huber, B.R., Silverman, M.A., Cline, M.M., Gill, T.B., Cross,

C.G., Cook, D.G., and Minoshima, S. (2021). Intranasal paclitaxel alters

Alzheimer’s disease phenotypic features in 3xTg-AD mice. J Alzheimer

Dis 83, 379–394.

Crous-Bou, M., Minguillón, C., Gramunt, N., and Molinuevo, J.L. (2017).

Alzheimer’s disease prevention: from risk factors to early intervention.

Alzheimers Res Ther 9, 71.

Crouzin, N., Baranger, K., Cavalier, M., Marchalant, Y., Cohen-Solal, C.,

Roman, F.S., Khrestchatisky, M., Rivera, S., Feron, F., and Vignes, M.

(2013). Area-specific alterations of synaptic plasticity in the 5XFAD

mouse model of Alzheimer’s disease: dissociation between somato-

sensory cortex and hippocampus. PLoS ONE 8, e74667.

Cummings, J., Lee, G., Nahed, P., Kambar, M.E.Z.N., Zhong, K., Fonseca,

J., and Taghva, K. (2022). Alzheimer’s disease drug development

pipeline: 2022. Alzheimers Dement 8, e12295.

Davis, J., Xu, F., Deane, R., Romanov, G., Previti, M.L., Zeigler, K.,

Zlokovic, B.V., and Van Nostrand, W.E. (2004). Early-onset and robust

cerebral microvascular accumulation of amyloid β-protein in transgenic

mice expressing low levels of a vasculotropic Dutch/Iowa mutant form

of amyloid β-protein precursor. J Biol Chem 279, 20296–20306.

Davis, J., Xu, F., Miao, J., Previti, M.L., Romanov, G., Ziegler, K., and Van

Nostrand, W.E. (2006). Deficient cerebral clearance of vasculotropic

mutant Dutch/Iowa double Aß in human AßPP transgenic mice.

Neurobiol Aging 27, 946–954.

de Oliveira, P., Cella, C., Locker, N., Ravindran, K.K.G., Mendis, A.,

Wafford, K., Gilmour, G., Dijk, D.J., and Winsky-Sommerer, R. (2022).

Improved sleep, memory, and cellular pathological features of

tauopathy, including the NLRP3 inflammasome, after chronic

administration of trazodone in rTg4510 mice. J Neurosci 42, 3494–

3509.

Decker, J.M., Krüger, L., Sydow, A., Dennissen, F.J., Siskova, Z.,

Mandelkow, E., and Mandelkow, E. (2016). The Tau/A152T

mutation, a risk factor for frontotemporal-spectrum disorders, leads to

NR2B receptor-mediated excitotoxicity. EMBO Rep 17, 552–569.

Decker, J.M., Krüger, L., Sydow, A., Zhao, S., Frotscher, M., Mandelkow,

E., and Mandelkow, E.M. (2015). Pro-aggregant Tau impairs mossy

fiber plasticity due to structural changes and Ca++ dysregulation. Acta

Neuropathol Commun 3, 23.

Delrieu, J., Bateman, R.J., Touchon, J., Sabbagh, M., and Cummings, J.

(2022). The future of AD clinical trials with the advent of anti-amyloid

therapies: an CTAD Task force report. J Prev Alzheimers Dis 9, 393–

34 Li, X., et al. Sci China Life Sci

399.

Dennissen, F.J.A., Anglada-Huguet, M., Sydow, A., Mandelkow, E., and

Mandelkow, E.M. (2016). Adenosine A1receptor antagonist rolofylline

alleviates axonopathy caused by human Tau ΔK280. Proc Natl Acad Sci

USA 113, 11597–11602.

Dewachter, I., Van Dorpe, J., Smeijers, L., Gilis, M., Kuipéri, C., Laenen,

I., Caluwaerts, N., Moechars, D., Checler, F., Vanderstichele, H., et al.

(2000). Aging increased amyloid peptide and caused amyloid plaques in

brain of old APP/V717I transgenic mice by a different mechanism than

mutant presenilin1. J Neurosci 20, 6452–6458.

Dodart, J.C., Meziane, H., Mathis, C., Bales, K.R., Paul, S.M., and

Ungerer, A. (1999). Behavioral disturbances in transgenic mice

overexpressing the V717F Β-amyloid precursor protein. Behav

Neurosci 113, 982–990.

Dodiya, H.B., Frith, M., Sidebottom, A., Cao, Y., Koval, J., Chang, E., and

Sisodia, S.S. (2020). Synergistic depletion of gut microbial consortia,

but not individual antibiotics, reduces amyloidosis in APPPS1-21

Alzheimer’s transgenic mice. Sci Rep 10, 8183.

Dodiya, H.B., Lutz, H.L., Weigle, I.Q., Patel, P., Michalkiewicz, J., Roman-

Santiago, C.J., Zhang, C.M., Liang, Y., Srinath, A., Zhang, X., et al.

(2022). Gut microbiota-driven brain Aβ amyloidosis in mice requires

microglia. J Exp Med 219.

Domnitz, S.B., Robbins, E.M., Hoang, A.W., Garcia-Alloza, M., Hyman,

B.T., Rebeck, G.W., Greenberg, S.M., Bacskai, B.J., and Frosch, M.P.

(2005). Progression of cerebral amyloid angiopathy in transgenic mouse

models of Alzheimer disease. J Neuropathol Exp Neurol 64, 588–594.

Drummond, E., and Wisniewski, T. (2017). Alzheimer’s disease:

experimental models and reality. Acta Neuropathol 133, 155–175.

Dudal, S., Krzywkowski, P., Paquette, J., Morissette, C., Lacombe, D.,

Tremblay, P., and Gervais, F. (2004). Inflammation occurs early during

the Aβ deposition process in TgCRND8 mice. Neurobiol Aging 25,

861–871.

Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C.M., Perez-Tur, J., Hutton,

M., Buee, L., Harigaya, Y., Yager, D., et al. (1996). Increased amyloid-

β42(43) in brains of mice expressing mutant presenilin 1. Nature 383,

710–713.

Eckermann, K., Mocanu, M.M., Khlistunova, I., Biernat, J., Nissen, A.,

Hofmann, A., Schönig, K., Bujard, H., Haemisch, A., Mandelkow, E., et

al. (2007). The β-propensity of Tau determines aggregation and synaptic

loss in inducible mouse models of tauopathy. J Biol Chem 282, 31755–

31765.

Elder, G.A., Gama Sosa, M.A., De Gasperi, R., Dickstein, D.L., and Hof, P.

R. (2010). Presenilin transgenic mice as models of Alzheimer’s disease.

Brain Struct Funct 214, 127–143.

Elhaik Goldman, S., Goez, D., Last, D., Naor, S., Liraz Zaltsman, S.,

Sharvit-Ginon, I., Atrakchi-Baranes, D., Shemesh, C., Twitto-

Greenberg, R., Tsach, S., et al. (2018). High-fat diet protects the

blood-brain barrier in an Alzheimer’s disease mouse model. Aging Cell

17, e12818.

Evans, C.E., Thomas, R.S., Freeman, T.J., Hvoslef-Eide, M., Good, M.A.,

and Kidd, E.J. (2019). Selective reduction of APP-BACE1 activity

improves memory via NMDA-NR2B receptor-mediated mechanisms in

aged PDAPP mice. Neurobiol Aging 75, 136–149.

Fan, R., Xu, F., Previti, M.L., Davis, J., Grande, A.M., Robinson, J.K., and

Van Nostrand, W.E. (2007). Minocycline reduces microglial activation

and improves behavioral deficits in a transgenic model of cerebral

microvascular amyloid. J Neurosci 27, 3057–3063.

Fernandez-Funez, P., de Mena, L., and Rincon-Limas, D.E. (2015).

Modeling the complex pathology of Alzheimer’s disease in

Drosophila.Exp Neurol 274, 58–71.

Ferretti, M.T., Bruno, M.A., Ducatenzeiler, A., Klein, W.L., and Cuello, A.

C. (2012). Intracellular Aβ-oligomers and early inflammation in a

model of Alzheimer’s disease. Neurobiol Aging 33, 1329–1342.

Ferretti, M.T., Partridge, V., C. Leon, W., Canneva, F., Allard, S., N.

Arvanitis, D., Vercauteren, F., Houle, D., Ducatenzeiler, A., L. Klein,

W., et al. (2011). Transgenic mice as a model of pre-clinical Alzheimers

disease. Curr Alzheimer Res 8, 4–23.

Flanigan, T.J., Xue, Y., Kishan Rao, S., Dhanushkodi, A., and McDonald,

M.P. (2014). Abnormal vibrissa-related behavior and loss of barrel field

inhibitory neurons in 5xFAD transgenics. Genes Brain Behav 13, 488–

500.

Foster, J.B., Lashley, R., Zhao, F., Wang, X., Kung, N., Askwith, C.C., Lin,

L., Shultis, M.W., Hodgetts, K.J., and Lin, C.L.G. (2019). Enhancement

of tripartite synapses as a potential therapeutic strategy for Alzheimer’s

disease: a preclinical study in rTg4510 mice. Alzheimers Res Ther 11,

75.

Frautschy, S.A., Yang, F., Irrizarry, M., Hyman, B., Saido, T.C., Hsiao, K.,

and Cole, G.M. (1998). Microglial response to amyloid plaques in

APPsw transgenic mice. Am J Pathol 152, 307–317.

Friedrich, G., and Soriano, P. (1991). Promoter traps in embryonic stem

cells: a genetic screen to identify and mutate developmental genes in

mice. Genes Dev 5, 1513–1523.

Frost, J.L., Liu, B., Rahfeld, J.U., Kleinschmidt, M., O’Nuallain, B., Le, K.

X., Lues, I., Caldarone, B.J., Schilling, S., Demuth, H.U., et al. (2015).

An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves

cognition in APPswe/PS1ΔE9 mice. Neurobiol Aging 36, 3187–3199.

Gaj, T., Gersbach, C.A., and Barbas Iii, C.F. (2013). ZFN, TALEN, and

CRISPR/Cas-based methods for genome engineering. Trends

Biotechnol 31, 397–405.

Gamage, K.K., and Kumar, S. (2017). Aducanumab therapy ameliorates

calcium overload in a mouse model of Alzheimer’s disease. J Neurosci

37, 4430–4432.

Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P.,

Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al.

(1995). Alzheimer-type neuropathology in transgenic mice

overexpressing V717F β-amyloid precursor protein. Nature 373, 523–

527.

Gandy, S., Simon, A.J., Steele, J.W., Lublin, A.L., Lah, J.J., Walker, L.C.,

Levey, A.I., Krafft, G.A., Levy, E., Checler, F., et al. (2010). Days to

criterion as an indicator of toxicity associated with human Alzheimer

amyloid-β oligomers. Ann Neurol 68, 220–230.

Garcia-Alloza, M., Robbins, E.M., Zhang-Nunes, S.X., Purcell, S.M.,

Betensky, R.A., Raju, S., Prada, C., Greenberg, S.M., Bacskai, B.J., and

Frosch, M.P. (2006). Characterization of amyloid deposition in the

APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24,

516–524.

Garrick, D., Fiering, S., Martin, D.I.K., and Whitelaw, E. (1998). Repeat-

induced gene silencing in mammals. Nat Genet 18, 56–59.

Gauthier, S., Wu, L., Rosa-Neto, P., and Jia, J. (2012). Prevention strategies

for Alzheimer’s disease. Transl Neurodegener 1, 13.

Gelman, S., Palma, J., Tombaugh, G., and Ghavami, A. (2018). Differences

in synaptic dysfunction between rTg4510 and APP/PS1 mouse models

of Alzheimer’s disease. J Alzheimer Dis 61, 195–208.

Gengler, S., Hamilton, A., and Holscher, C. (2010). Synaptic plasticity in

the hippocampus of a APP/PS1 mouse model of Alzheimer’s disease is

impaired in old but not young mice. PLoS ONE 5, e9764.

Giannoni, P., Arango-Lievano, M., Neves, I.D., Rousset, M.C., Baranger,

K., Rivera, S., Jeanneteau, F., Claeysen, S., and Marchi, N. (2016).

Cerebrovascular pathology during the progression of experimental

Alzheimer’s disease. Neurobiol Dis 88, 107–117.

Gjoneska, E., Pfenning, A.R., Mathys, H., Quon, G., Kundaje, A., Tsai, L.

H., and Kellis, M. (2015). Conserved epigenomic signals in mice and

humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–

369.

Goodwin, M.S., Sinyavskaya, O., Burg, F., O’Neal, V., Ceballos-Diaz, C.,

Cruz, P.E., Lewis, J., Giasson, B.I., Davies, P., Golde, T.E., et al. (2021).

Anti-tau scFvs targeted to the cytoplasm or secretory pathway variably

modify pathology and neurodegenerative phenotypes. Mol Ther 29,

859–872.

Gordon, M.N., Holcomb, L.A., Jantzen, P.T., DiCarlo, G., Wilcock, D.,

Boyett, K.W., Connor, K., Melachrino, J., O’Callaghan, J.P., and

Morgan, D. (2002). Time course of the development of Alzheimer-like

pathology in the doubly transgenic PS1+APP mouse. Exp Neurol 173,

183–195.

Li, X., et al. Sci China Life Sci

Götz, J., Bodea, L.G., and Goedert, M. (2018). Rodent models for

Alzheimer disease. Nat Rev Neurosci 19, 583–598.

Govindarajan, N., Agis-Balboa, R.C., Walter, J., Sananbenesi, F., and

Fischer, A. (2011). Sodium butyrate improves memory function in an

Alzheimer’s disease mouse model when administered at an advanced

stage of disease progression. J Alzheimer Dis 26, 187–197.

Gratuze, M., Leyns, C.E.G., Sauerbeck, A.D., St-Pierre, M.K., Xiong, M.,

Kim, N., Serrano, J.R., Tremblay, M.È., Kummer, T.T., Colonna, M., et

al. (2020). Impact of TREM2R47H variant on tau pathology-induced

gliosis and neurodegeneration. J Clin Invest 130, 4954–4968.

Grueninger, F., Bohrmann, B., Czech, C., Ballard, T.M., Frey, J.R.,

Weidensteiner, C., von Kienlin, M., and Ozmen, L. (2010).

Phosphorylation of Tau at S422 is enhanced by Aβ in TauPS2APP

triple transgenic mice. Neurobiol Dis 37, 294–306.

Gunawardena, S., and Goldstein, L.S.B. (2001). Disruption of axonal

transport and neuronal viability by amyloid precursor protein mutations

in Drosophila.Neuron 32, 389–401.

Guo, Q., Fu, W., Sopher, B.L., Miller, M.W., Ware, C.B., Martin, G.M., and

Mattson, M.P. (1999). Increased vulnerability of hippocampal neurons

to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med

5, 101–106.

Hafezparast, M., Ahmad-Annuar, A., Wood, N.W., Tabrizi, S.J., and Fisher,

E.M. (2002). Mouse models for neurological disease. Lancet Neurol 1,

215–224.

Hampton, D.W., Webber, D.J., Bilican, B., Goedert, M., Spillantini, M.G.,

and Chandran, S. (2010). Cell-mediated neuroprotection in a mouse

model of human tauopathy. J Neurosci 30, 9973–9983.

Hara, M., Hirokawa, K., Kamei, S., and Uchihara, T. (2013). Isoform

transition from four-repeat to three-repeat tau underlies dendrosomatic

and regional progression of neurofibrillary pathology. Acta Neuropathol

125, 565–579.

Hartman, R.E., Izumi, Y., Bales, K.R., Paul, S.M., Wozniak, D.F., and

Holtzman, D.M. (2005). Treatment with an amyloid-β antibody

ameliorates plaque load, learning deficits, and hippocampal long-term

potentiation in a mouse model of Alzheimer’s disease. J Neurosci 25,

6213–6220.

Hashimoto, S., Matsuba, Y., Kamano, N., Mihira, N., Sahara, N., Takano,

J., Muramatsu, S., Saido, T.C., and Saito, T. (2019). Tau binding protein

CAPON induces tau aggregation and neurodegeneration. Nat Commun

10, 2394.

Havas, D., Hutter-Paier, B., Ubhi, K., Rockenstein, E., Crailsheim, K.,

Masliah, E., and Windisch, M. (2011). A longitudinal study of

behavioral deficits in an AβPP transgenic mouse model of

Alzheimer’s disease. J Alzheimer Dis 25, 231–243.

He, A., Zhang, C., Ke, X., Yi, Y., Yu, Q., Zhang, T., Yu, H., Du, H., Li, H.,

Tian, Q., et al. (2022). VGLUT3 neurons in median raphe control the

efficacy of spatial memory retrieval via ETV4 regulation of VGLUT3

transcription. Sci China Life Sci 65, 1590–1607.

Heckmann, B.L., Teubner, B.J.W., Boada-Romero, E., Tummers, B., Guy,

C., Fitzgerald, P., Mayer, U., Carding, S., Zakharenko, S.S., Wileman,

T., et al. (2020). Noncanonical function of an autophagy protein

prevents spontaneous Alzheimer’s disease. Sci Adv 6, eabb9036.

Helboe, L., Egebjerg, J., Barkholt, P., and Volbracht, C. (2017). Early

depletion of CA1 neurons and late neurodegeneration in a mouse

tauopathy model. Brain Res 1665, 22–35.

Herzig, M.C., Winkler, D.T., Burgermeister, P., Pfeifer, M., Kohler, E.,

Schmidt, S.D., Danner, S., Abramowski, D., Stürchler-Pierrat, C.,

Bürki, K., et al. (2004). Aβ is targeted to the vasculature in a mouse

model of hereditary cerebral hemorrhage with amyloidosis. Nat

Neurosci 7, 954–960.

Heuer, E., F. Rosen, R., Cintron, A., and C. Walker, L. (2012). Nonhuman

primate models of Alzheimer-like cerebral proteopathy. Curr Pharm

Des 18, 1159–1169.

Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen,

P., Wright, K., Saad, I., Mueller, R., Morgan, D., et al. (1998).

Accelerated Alzheimer-type phenotype in transgenic mice carrying both

mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med

4, 97–100.

Hole, K.L., Staniaszek, L.E., Menon Balan, G., Mason, J.M., Brown, J.T.,

and Williams, R.J. (2021). Oral (−)-epicatechin inhibits progressive tau

pathology in rTg4510 mice independent of direct actions at GSK3β.

Front Neurosci 15, 697319.

Hong, S., Beja-Glasser, V.F., Nfonoyim, B.M., Frouin, A., Li, S.,

Ramakrishnan, S., Merry, K.M., Shi, Q., Rosenthal, A., Barres, B.A.,

et al. (2016). Complement and microglia mediate early synapse loss in

Alzheimer mouse models. Science 352, 712–716.

Hoover, B.R., Reed, M.N., Su, J., Penrod, R.D., Kotilinek, L.A., Grant, M.

K., Pitstick, R., Carlson, G.A., Lanier, L.M., Yuan, L.L., et al. (2010).

Tau mislocalization to dendritic spines mediates synaptic dysfunction

independently of neurodegeneration. Neuron 68, 1067–1081.

Hou, T.T., Yang, H.Y., Wang, W., Wu, Q.Q., Tian, Y.R., and Jia, J.P. (2018).

Sulforaphane inhibits the generation of amyloid-β oligomer and

promotes spatial learning and memory in Alzheimer’s disease

(PS1V97L) transgenic mice. J Alzheimer Dis 62, 1803–1813.

Howlett, D.R., Bowler, K., Soden, P.E., Riddell, D., Davis, J.B., Richard-

son, J.C., Burbidge, S.A., Gonzalez, M.I., Irving, E.A., Lawman, A., et

al. (2008). Abeta deposition and related pathology in an APP x PS1

transgenic mouse model of Alzheimer’s disease. Histol Histopathol 23,

67–76.

Howlett, D.R., Richardson, J.C., Austin, A., Parsons, A.A., Bate, S.T.,

Davies, D.C., and Gonzalez, M.I. (2004). Cognitive correlates of Aβ

deposition in male and female mice bearing amyloid precursor protein

and presenilin-1 mutant transgenes. Brain Res 1017, 130–136.

Hsia, A.Y., Masliah, E., McConlogue, L., Yu, G.Q., Tatsuno, G., Hu, K.,

Kholodenko, D., Malenka, R.C., Nicoll, R.A., and Mucke, L. (1999).

Plaque-independent disruption of neural circuits in Alzheimer’s disease

mouse models. Proc Natl Acad Sci USA 96, 3228–3233.

Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S.,

Yang, F., and Cole, G. (1996). Correlative memory deficits, Aβ

elevation, and amyloid plaques in transgenic mice. Science 274, 99–

103.

Hu, X., Das, B., Hou, H., He, W., and Yan, R. (2018). BACE1 deletion in

the adult mouse reverses preformed amyloid deposition and improves

cognitive functions. J Exp Med 215, 927–940.

Huang, K., Marcora, E., Pimenova, A.A., Di Narzo, A.F., Kapoor, M., Jin,

S.C., Harari, O., Bertelsen, S., Fairfax, B.P., Czajkowski, J., et al.

(2017). A common haplotype lowers PU.1 expression in myeloid cells

and delays onset of Alzheimer’s disease. Nat Neurosci 20, 1052–1061.

Hwang, D.Y., Chae, K.R., Kang, T.S., Hwang, J.H., Lim, C.H., Kang, H.K.,

Goo, J.S., Lee, M.R., Lim, H.J., Min, S.H., et al. (2002). Alterations in

behavior, amyloid p-42, caspase-3, and Cox-2 in mutant PS2 transgenic

mouse model of Alzheimer’s disease. FASEB J 16, 805–813.

Hwang, D.Y., Cho, J.S., Lee, S.H., Chae, K.R., Lim, H.J., Min, S.H., Seo,

S.J., Song, Y.S., Song, C.W., Paik, S.G., et al. (2004). Aberrant

expressions of pathogenic phenotype in Alzheimer’s diseased

transgenic mice carrying NSE-controlled APPsw. Exp Neurol 186,

20–32.

Hyman, B., and Tanzi, R.E. (2019). Effects of species-specific genetics on

Alzheimer’s mouse models. Neuron 101, 351–352.

Irizarry, M.C., Mcnamara, M., Fedorchak, K., Hsiao, K., and Hyman, B.T.

(1997). APPSW transgenic mice develop age-related Aβ deposits and

neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp

Neurol 56, 965–973.

Jackson, H.M., Soto, I., Graham, L.C., Carter, G.W., and Howell, G.R.

(2013). Clustering of transcriptional profiles identifies changes to

insulin signaling as an early event in a mouse model of Alzheimer’s

disease. BMC Genomics 14, 831.

Jackson, R.J., Rudinskiy, N., Herrmann, A.G., Croft, S., Kim, J.M., Pet-

rova, V., Ramos-Rodriguez, J.J., Pitstick, R., Wegmann, S., Garcia-

Alloza, M., Carlson, G.A., Hyman, B.T., and Spires-Jones, T.L. (2016).

Human tau increases amyloid beta plaque size but not amyloid beta-

mediated synapse loss in a novel mouse model of Alzheimer’s disease.

Eur J Neurosci 44, 3056–3066.

Jacobsen, J.S., Wu, C.C., Redwine, J.M., Comery, T.A., Arias, R., Bowlby,

36 Li, X., et al. Sci China Life Sci

M., Martone, R., Morrison, J.H., Pangalos, M.N., Reinhart, P.H., et al.

(2006). Early-onset behavioral and synaptic deficits in a mouse model

of Alzheimer’s disease. Proc Natl Acad Sci USA 103, 5161–5166.

Jaenisch, R., and Mintz, B. (1974). Simian virus 40 DNA sequences in

DNA of healthy adult mice derived from preimplantation blastocysts

injected with viral DNA. Proc Natl Acad Sci USA 71, 1250–1254.

Jankowsky, J.L., Fadale, D.J., Anderson, J., Xu, G.M., Gonzales, V.,

Jenkins, N.A., Copeland, N.G., Lee, M.K., Younkin, L.H., Wagner, S.

L., et al. (2004). Mutant presenilins specifically elevate the levels of the

42 residue β-amyloid peptide in vivo: evidence for augmentation of a

42-specific γ secretase. Hum Mol Genet 13, 159–170.

Jankowsky, J.L., Slunt, H.H., Gonzales, V., Savonenko, A.V., Wen, J.C.,

Jenkins, N.A., Copeland, N.G., Younkin, L.H., Lester, H.A., Younkin,

S.G., et al. (2005). Persistent amyloidosis following suppression of

Abeta production in a transgenic model of Alzheimer disease. PLoS

Med 2, e355.

Jankowsky, J.L., Slunt, H.H., Ratovitski, T., Jenkins, N.A., Copeland, N.G.,

and Borchelt, D.R. (2001). Co-expression of multiple transgenes in

mouse CNS: a comparison of strategies. Biomol Eng 17, 157–165.

Jawhar, S., Trawicka, A., Jenneckens, C., Bayer, T.A., and Wirths, O.

(2012). Motor deficits, neuron loss, and reduced anxiety coinciding with

axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD

mouse model of Alzheimer’s disease. Neurobiol Aging 33, 196.e29–

196.e40.

Jay, T.R., Hirsch, A.M., Broihier, M.L., Miller, C.M., Neilson, L.E.,

Ransohoff, R.M., Lamb, B.T., and Landreth, G.E. (2017). Disease

progression-dependent effects of TREM2 deficiency in a mouse model

of Alzheimer’s disease. J Neurosci 37, 637–647.

Jia, J., Xu, E., Shao, Y., Jia, J., Sun, Y., and Li, D. (2005). One novel

presenilin-1 gene mutation in a Chinese pedigree of familial

Alzheimer’s disease. J Alzheimer Dis 7, 119–124. ; discussion 173-180.

Jia, L., Du, Y., Chu, L., Zhang, Z., Li, F., Lyu, D., Li, Y., Li, Y., Zhu, M.,

Jiao, H., et al. (2020a). Prevalence, risk factors, and management of

dementia and mild cognitive impairment in adults aged 60 years or

older in China: a cross-sectional study. Lancet Public Health 5, e661–

e671.

Jia, L., Fu, Y., Shen, L., Zhang, H., Zhu, M., Qiu, Q., Wang, Q., Yan, X.,

Kong, C., Hao, J., et al. (2020b). PSEN1,PSEN2, and APP mutations in

404 Chinese pedigrees with familial Alzheimer’s disease. Alzheimers

Dement 16, 178–191.

Jia, L., Quan, M., Fu, Y., Zhao, T., Li, Y., Wei, C., Tang, Y., Qin, Q., Wang,

F., Qiao, Y., et al. (2020c). Dementia in China: epidemiology, clinical

management, and research advances. Lancet Neurol 19, 81–92.

Jiao, H., and Jia, J. (2022). Ginsenoside compound K acts via LRP1 to

alleviate Amyloid β42-induced neuroinflammation in microglia by

suppressing NF-κB. Biochem Biophys Res Commun 590, 14–19.

Josephine Boder, E., and Banerjee, I.A. (2021). Alzheimer’s disease:

current perspectives and advances in physiological modeling.

Bioengineering 8, 211.

Kamphuis, W., Mamber, C., Moeton, M., Kooijman, L., Sluijs, J.A., Jansen,

A.H., Verveer, M., de Groot, L.R., Smith, V.D., Rangarajan, S., et al.

(2012). GFAP isoforms in adult mouse brain with a focus on neurogenic

astrocytes and reactive astrogliosis in mouse models of Alzheimer

disease. PLoS ONE 7, e42823.

Kang, S., Kim, J., and Chang, K.A. (2021). Spatial memory deficiency

early in 6xTg Alzheimer’s disease mouse model. Sci Rep 11, 1334.

Karran, E., and De Strooper, B. (2022). The amyloid hypothesis in

Alzheimer disease: new insights from new therapeutics. Nat Rev Drug

Discov 21, 306–318.

Karran, E., and Hardy, J. (2014). A critique of the drug discovery and phase

3 clinical programs targeting the amyloid hypothesis for Alzheimer

disease. Ann Neurol 76, 185–205.

Kawasumi, M., Chiba, T., Yamada, M., Miyamae-Kaneko, M., Matsuoka,

M., Nakahara, J., Tomita, T., Iwatsubo, T., Kato, S., Aiso, S., et al.

(2004). Targeted introduction of V642I mutation in amyloid precursor

protein gene causes functional abnormality resembling early stage of

Alzheimer’s disease in aged mice. Eur J Neurosci 19, 2826–2838.

Kelly, P.H., Bondolfi, L., Hunziker, D., Schlecht, H.P., Carver, K., Maguire,

E., Abramowski, D., Wiederhold, K.H., Sturchler-Pierrat, C., Jucker,

M., et al. (2003). Progressive age-related impairment of cognitive

behavior in APP23 transgenic mice. Neurobiol Aging 24, 365–378.

Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-

Szternfeld, R., Ulland, T.K., David, E., Baruch, K., Lara-Astaiso, D.,

Toth, B., et al. (2017). A unique microglia type associated with

restricting development of Alzheimer’s disease. Cell 169, 1276–1290.

e17.

Kim, J., and Jeong, Y. (2015). In vivo image of cerebral amyloid angiopathy

in an Alzheimer’s disease mouse model. J Stroke 17, 87–88.

Kim, J.H., Nam, Y.P., Jeon, S.M., Han, H.S., and Suk, K. (2012). Amyloid

neurotoxicity is attenuated by metallothionein: dual mechanisms at

work. J Neurochem 121, 751–762.

Kimura, R., MacTavish, D., Yang, J., Westaway, D., and Jhamandas, J.H.

(2012). Beta amyloid-induced depression of hippocampal long-term

potentiation is mediated through the amylin receptor. J Neurosci 32,

17401–17406.

Kimura, R., and Ohno, M. (2009). Impairments in remote memory

stabilization precede hippocampal synaptic and cognitive failures in

5XFAD Alzheimer mouse model. Neurobiol Dis 33, 229–235.

King, A. (2018). The search for better animal models of Alzheimer’s

disease. Nature 559, S13–S15.

Klyubin, I., Walsh, D.M., Lemere, C.A., Cullen, W.K., Shankar, G.M.,

Betts, V., Spooner, E.T., Jiang, L., Anwyl, R., Selkoe, D.J., et al. (2005).

Amyloid β protein immunotherapy neutralizes Aβ oligomers that

disrupt synaptic plasticity in vivo.Nat Med 11, 556–561.

Knobloch, M., Farinelli, M., Konietzko, U., Nitsch, R.M., and Mansuy, I.

M. (2007a). Aβ oligomer-mediated long-term potentiation impairment

involves protein phosphatase 1-dependent mechanisms. J Neurosci 27,

7648–7653.

Knobloch, M., Konietzko, U., Krebs, D.C., and Nitsch, R.M. (2007b).

Intracellular Aβ and cognitive deficits precede β-amyloid deposition in

transgenic arcAβ mice. Neurobiol Aging 28, 1297–1306.

Kopeikina, K.J., Polydoro, M., Tai, H.C., Yaeger, E., Carlson, G.A.,

Pitstick, R., Hyman, B.T., and Spires-Jones, T.L. (2013). Synaptic

alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol

521, 1334–1353.

Kulnane, L.S., and Lamb, B.T. (2001). Neuropathological characterization

of mutant amyloid precursor protein yeast artificial chromosome

transgenic mice. Neurobiol Dis 8, 982–992.

Kurt, M.A., Davies, D.C., Kidd, M., Duff, K., and Howlett, D.R. (2003).

Hyperphosphorylated tau and paired helical filament-like structures in

the brains of mice carrying mutant amyloid precursor protein and

mutant presenilin-1 transgenes. Neurobiol Dis 14, 89–97.

Kwan, P., Ho, A., and Baum, L. (2022). Effects of deferasirox in

Alzheimer’s disease and tauopathy animal models. Biomolecules 12,

365.

Lalonde, R., Kim, H.D., Maxwell, J.A., and Fukuchi, K. (2005).

Exploratory activity and spatial learning in 12-month-old

APP695SWE/co+PS1/ΔE9 mice with amyloid plaques. Neurosci Lett

390, 87–92.

Lalonde, R., and Strazielle, C. (2005). PS1 knockin mice with the Japanese

I213T mutation: effects on exploratory activity, motor coordination, and

spatial learning. Behav Brain Res 162, 182–190.

Lamb, B.A., Bardel, K.A., Kulnane, L.S., Anderson, J.J., Holtz, G.,

Wagner, S.L., Sisodia, S.S., and Hoeger, E.J. (1999). Amyloid

production and deposition in mutant amyloid precursor protein and

presenilin-1 yeast artificial chromosome transgenic mice. Nat Neurosci

2, 695–697.

Lamb, B.T., Call, L.M., Slunt, H.H., Bardel, K.A., Lawler, A.M., Eckman,

C.B., Younkin, S.G., Holtz, G., Wagner, S.L., Price, D.L., et al. (1997).

Altered metabolism of familial Alzheimer’s disease-linked amyloid

precursor protein variants in yeast artificial chromosome transgenic

mice. Hum Mol Genet 6, 1535–1541.

Lambert, M.P., Velasco, P.T., Chang, L., Viola, K.L., Fernandez, S., Lacor,

P.N., Khuon, D., Gong, Y., Bigio, E.H., Shaw, P., et al. (2007).

Li, X., et al. Sci China Life Sci

Monoclonal antibodies that target pathological assemblies of Aβ. J

Neurochem 100, 23–35.

Lanz, T.A., Carter, D.B., and Merchant, K.M. (2003). Dendritic spine loss

in the hippocampus of young PDAPP and Tg2576 mice and its

prevention by the ApoE2 genotype. Neurobiol Dis 13, 246–253.

Larson, J., Lynch, G., Games, D., and Seubert, P. (1999). Alterations in

synaptic transmission and long-term potentiation in hippocampal slices

from young and aged PDAPP mice. Brain Res 840, 23–35.

Lasagna-Reeves, C.A., de Haro, M., Hao, S., Park, J., Rousseaux, M.W.C.,

Al-Ramahi, I., Jafar-Nejad, P., Vilanova-Velez, L., See, L., De Maio, A.,

et al. (2016). Reduction of Nuak1 decreases tau and reverses

phenotypes in a tauopathy mouse model. Neuron 92, 407–418.

Lee, C.Y.D., Daggett, A., Gu, X., Jiang, L.L., Langfelder, P., Li, X., Wang,

N., Zhao, Y., Park, C.S., Cooper, Y., et al. (2018). Elevated TREM2

gene dosage reprograms microglia responsivity and ameliorates

pathological phenotypes in Alzheimer’s disease models. Neuron 97,

1032–1048.e5.

Lee, H.J., Jeon, S.G., Kim, J., Kang, R.J., Kim, S.M., Han, K.M., Park, H.,

Kim, K.T., Sung, Y.M., Nam, H.Y., et al. (2021a). Ibrutinib modulates

Aβ/tau pathology, neuroinflammation, and cognitive function in mouse

models of Alzheimer’s disease. Aging Cell 20, e13332.

Lee, H.S., Kim, M.W., Jin, K.S., Shin, H.C., Kim, W.K., Lee, S.C., Kim, S.

J., Lee, E.W., and Ku, B. (2021b). Molecular analysis of the interaction

between human PTPN21 and the oncoprotein E7 from human

papillomavirus genotype 18. MolCells 44, 26–37.

Lefterov, I., Fitz, N.F., Cronican, A., Lefterov, P., Staufenbiel, M., and

Koldamova, R. (2009). Memory deficits in APP23/Abca1+/− mice

correlate with the level of Aβoligomers. ASN Neuro 1, AN20090015.

Lehman, E.J.H., Kulnane, L.S., and Lamb, B.T. (2003). Alterations in β-

amyloid production and deposition in brain regions of two transgenic

models. Neurobiol Aging 24, 645–653.

Leinenga, G., Koh, W.K., and Götz, J. (2021). A comparative study of the

effects of Aducanumab and scanning ultrasound on amyloid plaques

and behavior in the APP23 mouse model of Alzheimer disease.

Alzheimers Res Ther 13, 76.

Leon, W.C., Canneva, F., Partridge, V., Allard, S., Ferretti, M.T., DeWilde,

A., Vercauteren, F., Atifeh, R., Ducatenzeiler, A., Klein, W., et al.

(2010). A novel transgenic rat model with a full Alzheimer’s-like

amyloid pathology displays pre-plaque intracellular amyloid-β-

associated cognitive impairment. J Alzheimer Dis 20, 113–126.

Lewis, J., Dickson, D.W., Lin, W.L., Chisholm, L., Corral, A., Jones, G.,

Yen, S.H., Sahara, N., Skipper, L., Yager, D., et al. (2001). Enhanced

neurofibrillary degeneration in transgenic mice expressing mutant tau

and APP. Science 293, 1487–1491.

Lewis, J., McGowan, E., Rockwood, J., Melrose, H., Nacharaju, P., Van

Slegtenhorst, M., Gwinn-Hardy, K., Murphy, M.P., Baker, M., Yu, X., et

al. (2000). Neurofibrillary tangles, amyotrophy and progressive motor

disturbance in mice expressing mutant (P301L) tau protein. Nat Genet

25, 402–405.

Li, B., Xu, L., Li, F., Li, Y., Zhao, Y., Zhang, H., Quan, M., and Jia, J.

(2022). CaMKIIα signaling is required for the neuroprotective effects of

Dl-3-n-butylphthalide in Alzheimer’s disease. Mol Neurobiol 59, 3370–

3381.

Li, D., Qiu, Z., Shao, Y., Chen, Y., Guan, Y., Liu, M., Li, Y., Gao, N., Wang,

L., Lu, X., et al. (2013). Heritable gene targeting in the mouse and rat

using a CRISPR-Cas system. Nat Biotechnol 31, 681–683.

Li, F., Wu, X., Li, J., and Niu, Q. (2016). Ginsenoside Rg1 ameliorates

hippocampal long-term potentiation and memory in an Alzheimer’s

disease model. Mol Med Rep 13, 4904–4910.

Li, H., Jia, J., Wang, W., Hou, T., Tian,, Y., Wu, Q., Xu, L., Wei, Y., and

Wang, X. (2018). Honokiol alleviates cognitive deficits of Alzheimer’s

disease (PS1V97L) transgenic mice by activating mitochondrial SIRT3.

J Alzheimer Dis 64, 291–302.

Li, H.Q., Ip, S.P., Yuan, Q.J., Zheng, G.Q., Tsim, K.K.W., Dong, T.T.X.,

Lin, G., Han, Y., Liu, Y., Xian, Y.F., et al. (2019). Isorhynchophylline

ameliorates cognitive impairment via modulating amyloid pathology,

tau hyperphosphorylation and neuroinflammation: Studies in a

transgenic mouse model of Alzheimer’s disease. Brain Behav Immun

82, 264–278.

Li, S., Wu, Z., and Le, W. (2021a). Traditional Chinese medicine for

dementia. Alzheimers Dement 17, 1066–1071.

Li, T., Martin, E., Abada, Y., Boucher, C., Cès, A., Youssef, I., Fenaux, G.,

Forand, Y., Legrand, A., Nachiket, N., et al. (2020). Effects of chronic

masitinib treatment in APPswe/PSEN1dE9 transgenic mice modeling

Alzheimer’s disease. J Alzheimer Dis 76, 1339–1345.

Li, W., Pang, Y., Wang, Y., Mei, F., Guo, M., Wei, Y., Li, X., Qin, W.,

Wang, W., Jia, L., et al. (2023). Aberrant palmitoylation caused by a

ZDHHC21 mutation contributes to pathophysiology of Alzheimer's

disease. BMC Med 21, 223.

Li, W., Wang, S., Zhang, H., Li, B., Xu, L., Li, Y., Kong, C., Jiao, H.,

Wang, Y., Pang, Y., et al. (2021b). Honokiol restores microglial pha-

gocytosis by reversing metabolic reprogramming. J Alzheimers Dis 82,

1475–1485.

Lillehaug, S., Syverstad, G.H., Nilsson, L.N.G., Bjaalie, J.G., Leergaard, T.

B., and Torp, R. (2014). Brainwide distribution and variance of

amyloid-beta deposits in tg-ArcSwe mice. Neurobiol Aging 35, 556–

564.

Liu, J., Baum, L., Yu, S., Lin, Y., Xiong, G., Chang, R.C.C., So, K.F., and

Chiu, K. (2021a). Preservation of retinal function through synaptic

stabilization in Alzheimer’s disease model mouse retina by lycium

barbarum extracts. Front Aging Neurosci 13, 788798.

Liu, P., Paulson, J.B., Forster, C.L., Shapiro, S.L., Ashe, K.H., and Zahs, K.

R. (2015). Characterization of a novel mouse model of Alzheimer’s

disease—amyloid pathology and unique β-amyloid oligomer profile.

PLoS ONE 10, e0126317.

Liu, W., Li, Y., Li, Y., Xu, L., and Jia, J. (2023). Carnosic acid attenuates

AβOs-induced apoptosis and synaptic impairment via regulating

NMDAR2B and its downstream cascades in SH-SY5Y cells. Mol

Neurobiol 60, 133–144.

Liu, X., Zhou, Q., Zhang, J.H., Wang, K.Y., Saito, T., Saido, T.C., Wang,

X., Gao, X., and Azuma, K. (2021b). Microglia-based sex-biased

neuropathology in early-stage Alzheimer’s disease model mice and the

potential pharmacologic efficacy of dioscin. Cells 10, 3261.

Liu, Y., Yao, J., Song, Z., Guo, W., Sun, B., Wei, J., Estillore, J.P., Back, T.

G., and Chen, S.R.W. (2021c). Limiting RyR2 open time prevents

Alzheimer’s disease-related deficits in the 3xTG-AD mouse model. J

Neurosci Res 99, 2906–2921.

Lo, A.C., Tesseur, I., Scopes, D.I.C., Nerou, E., Callaerts-Vegh, Z.,

Vermaercke, B., Treherne, J.M., De Strooper, B., and D’Hooge, R.

(2013). Dose-dependent improvements in learning and memory deficits

in APPPS1-21 transgenic mice treated with the orally active Aβ toxicity

inhibitor SEN1500. Neuropharmacology 75, 458–466.

Long, J.M., and Holtzman, D.M. (2019). Alzheimer disease: an update on

pathobiology and treatment strategies. Cell 179, 312–339.

Lord, A., Englund, H., Söderberg, L., Tucker, S., Clausen, F., Hillered, L.,

Gordon, M., Morgan, D., Lannfelt, L., Pettersson, F.E., et al. (2009).

Amyloid-β protofibril levels correlate with spatial learning in Arctic

Alzheimer’s disease transgenic mice. FEBS J 276, 995–1006.

Lord, A., Kalimo, H., Eckman, C., Zhang, X.Q., Lannfelt, L., and Nilsson,

L.N.G. (2006). The Arctic Alzheimer mutation facilitates early

intraneuronal Aβ aggregation and senile plaque formation in

transgenic mice. Neurobiol Aging 27, 67–77.

Lord, A., Philipson, O., Klingstedt, T., Westermark, G., Hammarström, P.,

Nilsson, K.P.R., and Nilsson, L.N.G. (2011). Observations in APP

bitransgenic mice suggest that diffuse and compact plaques form via

independent processes in Alzheimer’s disease. Am J Pathol 178, 2286–

2298.

Lyu, D., and Jia, J. (2022). Cryptotanshinone attenuates amyloid-β42-

induced tau phosphorylation by regulating PI3K/Akt/GSK3β pathway

in HT22 cells. Mol Neurobiol 59, 4488–4500.

Maeda, S., Djukic, B., Taneja, P., Yu, G., Lo, I., Davis, A., Craft, R., Guo,

W., Wang, X., Kim, D., et al. (2016). Expression of A152T human tau

causes age-dependent neuronal dysfunction and loss in transgenic mice.

EMBO Rep 17, 530–551.

38 Li, X., et al. Sci China Life Sci

Malm, T.M., Iivonen, H., Goldsteins, G., Keksa-Goldsteine, V., Ahtoniemi,

T., Kanninen, K., Salminen, A., Auriola, S., Van Groen, T., Tanila, H., et

al. (2007). Pyrrolidine dithiocarbamate activates Akt and improves

spatial learning in APP/PS1 mice without affecting β-amyloid burden. J

Neurosci 27, 3712–3721.

Marazuela, P., Paez-Montserrat, B., Bonaterra-Pastra, A., Solé, M., and

Hernández-Guillamon, M. (2022). Impact of cerebral amyloid

angiopathy in two transgenic mouse models of cerebral β-

amyloidosis: a neuropathological study. Int J Mol Sci 23, 4972.

Martini, A.C., Forner, S., Trujillo-Estrada, L., Baglietto-Vargas, D., and

LaFerla, F.M. (2018). Past to future: what animal models have taught us

about Alzheimer’s disease. J Alzheimers Dis 64, S365–S378.

Masliah, E., Sisk, A., Mallory, M., and Games, D. (2001). Neurofibrillary

pathology in transgenic mice overexpressing V717F β-amyloid

precursor protein. J Neuropathol Exp Neurol 60, 357–368.

Maurin, H., Chong, S.A., Kraev, I., Davies, H., Kremer, A., Seymour, C.

M., Lechat, B., Jaworski, T., Borghgraef, P., Devijver, H., et al. (2014).

Early structural and functional defects in synapses and myelinated ax-

ons in stratum lacunosum moleculare in two preclinical models for

tauopathy. PLoS ONE 9, e87605.

McGowan, E., Sanders, S., Iwatsubo, T., Takeuchi, A., Saido, T., Zehr, C.,

Yu, X., Uljon, S., Wang, R., Mann, D., et al. (1999). Amyloid phenotype

characterization of transgenic mice overexpressing both mutant amyloid

precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis 6,

231–244.

Mckean, N.E., Handley, R.R., and Snell, R.G. (2021). A review of the

current mammalian models of Alzheimer’s disease and challenges that

need to be overcome. Int J Mol Sci 22, 13168.

Mehla, J., Lacoursiere, S.G., Lapointe, V., McNaughton, B.L., Sutherland,

R.J., McDonald, R.J., and Mohajerani, M.H. (2019). Age-dependent

behavioral and biochemical characterization of single APP knock-in

mouse (APPNL-G-F/NL-G-F) model of Alzheimer’s disease. Neurobiol

Aging 75, 25–37.

Mei, Z., Zhang, F., Tao, L., Zheng, W., Cao, Y., Wang, Z., Tang, S., Le, K.,

Chen, S., Pi, R., et al. (2009). Cryptotanshinone, a compound from

Salvia miltiorrhiza modulates amyloid precursor protein metabolism

and attenuates β-amyloid deposition through upregulating α-secretase in

vivo and in vitro.Neurosci Lett 452, 90–95.

Meilandt, W.J., Maloney, J.A., Imperio, J., Lalehzadeh, G., Earr, T.,

Crowell, S., Bainbridge, T.W., Lu, Y., Ernst, J.A., Fuji, R.N., et al.

(2019). Characterization of the selective in vitro and in vivo binding

properties of crenezumab to oligomeric Aβ. Alzheimers Res Ther 11,

97.

Meilandt, W.J., Ngu, H., Gogineni, A., Lalehzadeh, G., Lee, S.H.,

Srinivasan, K., Imperio, J., Wu, T., Weber, M., Kruse, A.J., et al.

(2020). Trem2 deletion reduces late-stage amyloid plaque

accumulation, elevates the Aβ42:Aβ40 ratio, and exacerbates axonal

dystrophy and dendritic spine loss in the PS2APP Alzheimer’s mouse

model. J Neurosci 40, 1956–1974.

Miao, J., Vitek, M.P., Xu, F., Previti, M.L., Davis, J., and Van Nostrand, W.

E. (2005a). Reducing cerebral microvascular amyloid-β protein

deposition diminishes regional neuroinflammation in vasculotropic

mutant amyloid precursor protein transgenic mice. J Neurosci 25, 6271–

6277.

Miao, J., Xu, F., Davis, J., Otte-Höller, I., Verbeek, M.M., and Van

Nostrand, W.E. (2005b). Cerebral microvascular amyloid β protein

deposition induces vascular degeneration and neuroinflammation in

transgenic mice expressing human vasculotropic mutant amyloid β

precursor protein. Am J Pathol 167, 505–515.

Migliore, L., and Coppedè, F. (2022). Gene-environment interactions in

Alzheimer disease: the emerging role of epigenetics. Nat Rev Neurol

18, 643–660.

Minkeviciene, R., Ihalainen, J., Malm, T., Matilainen, O., Keksa-

Goldsteine, V., Goldsteins, G., Iivonen, H., Leguit, N., Glennon, J.,

Koistinaho, J., et al. (2008). Age-related decrease in stimulated

glutamate release and vesicular glutamate transporters in APP/PS1

transgenic and wild-type mice. J Neurochem 105, 584–594.

Mocanu, M.M., Nissen, A., Eckermann, K., Khlistunova, I., Biernat, J.,

Drexler, D., Petrova, O., Schönig, K., Bujard, H., Mandelkow, E., et al.

(2008). The potential for β-structure in the repeat domain of tau protein

determines aggregation, synaptic decay, neuronal loss, and coassembly

with endogenous tau in inducible mouse models of tauopathy. J

Neurosci 28, 737–748.

Moechars, D., Dewachter, I., Lorent, K., Reversé, D., Baekelandt, V.,

Naidu, A., Tesseur, I., Spittaels, K., Haute, C.V.D., Checler, F., et al.

(1999). Early phenotypic changes in transgenic mice that overexpress

different mutants of amyloid precursor protein in brain. J Biol Chem

274, 6483–6492.

Mucke, L., Masliah, E., Yu, G.Q., Mallory, M., Rockenstein, E.M.,

Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., and

McConlogue, L. (2000). High-level neuronal expression of Aβ1–42 in

wild-type human amyloid protein precursor transgenic mice:

synaptotoxicity without plaque formation. J Neurosci 20, 4050–4058.

Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad,

B., and Lannfelt, L. (1992). A pathogenic mutation for probable

Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid.

Nat Genet 1, 345–347.

Mullane, K., and Williams, M. (2019). Preclinical models of Alzheimer’s

disease: relevance and translational validity. Curr Protoc Pharmacol 84,

e57.

Müller-Schiffmann, A., Herring, A., Abdel-Hafiz, L., Chepkova, A.N.,

Schäble, S., Wedel, D., Horn, A.H.C., Sticht, H., de Souza Silva, M.A.,

Gottmann, K., et al. (2016). Amyloid-β dimers in the absence of plaque

pathology impair learning and synaptic plasticity. Brain 139, 509–525.

Murata, N., Murakami, K., Ozawa, Y., Kinoshita, N., Irie, K., Shirasawa,

T., and Shimizu, T. (2010). Silymarin attenuated the amyloid β plaque

burden and improved behavioral abnormalities in an Alzheimer’s

disease mouse model. Biosci Biotechnol Biochem 74, 2299–2306.

Nagakura, A., Shitaka, Y., Yarimizu, J., and Matsuoka, N. (2013).

Characterization of cognitive deficits in a transgenic mouse model of

Alzheimer’s disease and effects of donepezil and memantine. Eur J

Pharmacol 703, 53–61.

Nakano, Y., Kondoh, G., Kudo, T., Imaizumi, K., Kato, M., Miyazaki, J.,

Tohyama, M., Takeda, J., and Takeda, M. (1999). Accumulation of

murine amyloidbeta42 in a gene-dosage-dependent manner in PS1

‘knock-in’ mice. Eur J Neurosci 11, 2577–2581.

Nedelec, T., Couvy-Duchesne, B., Monnet, F., Daly, T., Ansart, M.,

Gantzer, L., Lekens, B., Epelbaum, S., Dufouil, C., and Durrleman, S.

(2022). Identifying health conditions associated with Alzheimer’s

disease up to 15 years before diagnosis: an agnostic study of French

and British health records. Lancet Digital Health 4, e169–e178.

Nilsson, P., Saito, T., and Saido, T.C. (2014). New mouse model of

Alzheimer’s. ACS Chem Neurosci 5, 499–502.

Nott, A., Holtman, I.R., Coufal, N.G., Schlachetzki, J.C.M., Yu, M., Hu, R.,

Han, C.Z., Pena, M., Xiao, J., Wu, Y., et al. (2019). Brain cell type-

specific enhancer-promoter interactome maps and disease-risk

association. Science 366, 1134–1139.

O’Leary, T.P., Robertson, A., Chipman, P.H., Rafuse, V.F., and Brown, R.E.

(2018). Motor function deficits in the 12 month-old female 5xFAD

mouse model of Alzheimer’s disease. Behav Brain Res 337, 256–263.

O’Leary, T.P., Shin, S., Fertan, E., Dingle, R.N., Almuklass, A., Gunn, R.

K., Yu, Z., Wang, J., and Brown, R.E. (2017). Reduced acoustic startle

response and peripheral hearing loss in the 5xFAD mouse model of

Alzheimer’s disease. Genes Brain Behav 16, 554–563.

Oakley, H., Cole, S.L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-

Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006).

Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron

loss in transgenic mice with five familial Alzheimer’s disease

mutations: potential factors in amyloid plaque formation. J Neurosci

26, 10129–10140.

Oddo, S., Caccamo, A., Shepherd, J.D., Murphy, M.P., Golde, T.E., Kayed,

R., Metherate, R., Mattson, M.P., Akbari, Y., and LaFerla, F.M. (2003).

Triple-transgenic model of Alzheimer’s disease with plaques and

tangles. Neuron 39, 409–421.

Li, X., et al. Sci China Life Sci

Oddo, S., Caccamo, A., Tran, L., Lambert, M.P., Glabe, C.G., Klein, W.L.,

and LaFerla, F.M. (2006). Temporal profile of amyloid-β (Aβ)

oligomerization in an in vivo model of Alzheimer disease. J Biol

Chem 281, 1599–1604.

Ohno, M., Chang, L., Tseng, W., Oakley, H., Citron, M., Klein, W.L.,

Vassar, R., and Disterhoft, J.F. (2006). Temporal memory deficits in

Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J

Neurosci 23, 251–260.

Onos, K.D., Uyar, A., Keezer, K.J., Jackson, H.M., Preuss, C., Acklin, C.J.,

O’Rourke, R., Buchanan, R., Cossette, T.L., Sukoff Rizzo, S.J., et al.

(2019). Enhancing face validity of mouse models of Alzheimer’s dis-

ease with natural genetic variation. PLoS Genet 15, e1008155.

Ortí-Casañ, N., Zuhorn, I.S., Naudé, P.J.W., De Deyn, P.P., van Schaik, P.E.

M., Wajant, H., and Eisel, U.L.M. (2022). A TNF receptor 2 agonist

ameliorates neuropathology and improves cognition in an Alzheimer’s

disease mouse model. Proc Natl Acad Sci USA 119, e2201137119.

Overk, C.R., and Masliah, E. (2014). Toward a unified therapeutics

approach targeting putative amyloid-β oligomer receptors. Proc Natl

Acad Sci USA 111, 13680–13681.

Ozmen, L., Albientz, A., Czech, C., and Jacobsen, H. (2009). Expression of

transgenic APP mRNA is the key determinant for beta-amyloid

deposition in PS2APP transgenic mice. Neurodegener Dis 6, 29–36.

Pang, K., Jiang, R., Zhang, W., Yang, Z., Li, L.L., Shimozawa, M.,

Tambaro, S., Mayer, J., Zhang, B., Li, M., et al. (2022). An App knock-

in rat model for Alzheimer’s disease exhibiting Aβ and tau pathologies,

neuronal death and cognitive impairments. Cell Res 32, 157–175.

Pauls, E., Bayod, S., Mateo, L., Alcalde, V., Juan-Blanco, T., Sánchez-Soto,

M., Saido, T.C., Saito, T., Berrenguer-Llergo, A., Attolini, C.S.O., et al.

(2021). Identification and drug-induced reversion of molecular

signatures of Alzheimer’s disease onset and progression in AppNL-G-F,

AppNL-F, and 3xTg-AD mouse models. Genome Med 13, 168.

Pedram, A., Razandi, M., Deschenes, R.J., and Levin, E.R. (2012). DHHC-

7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol

Biol Cell 23, 188–199.

Peng, Y., Sun, J., Hon, S., Nylander, A.N., Xia, W., Feng, Y., Wang, X., and

Lemere, C.A. (2010). L-3-n-butylphthalide improves cognitive

impairment and reduces amyloid-beta in a transgenic model of

Alzheimer’s disease. J Neurosci 30, 8180–8189.

Pensalfini, A., Kim, S., Subbanna, S., Bleiwas, C., Goulbourne, C.N.,

Stavrides, P.H., Jiang, Y., Lee, J.H., Darji, S., Pawlik, M., et al. (2020).

Endosomal dysfunction induced by directly overactivating Rab5

recapitulates prodromal and neurodegenerative features of

Alzheimer’s disease. Cell Rep 33, 108420.

Perez, S.E., Raghanti, M.A., Hof, P.R., Kramer, L., Ikonomovic, M.D.,

Lacor, P.N., Erwin, J.M., Sherwood, C.C., and Mufson, E.J. (2013).

Alzheimer’s disease pathology in the neocortex and hippocampus of the

western lowland gorilla (Gorilla gorilla gorilla). J Comp Neurol 521,

4318–4338.

Peroutka, S.J. (2022). Defining demographic cohorts in clinical trial

populations using large electronic health records databases. Contemp

Clin Trials 121, 106890.

Petrushina, I., Hovakimyan, A., Harahap-Carrillo, I.S., Davtyan, H.,

Antonyan, T., Chailyan, G., Kazarian, K., Antonenko, M., Jullienne,

A., Hamer, M.M., et al. (2020). Characterization and preclinical

evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter

the first-in-human clinical trials. Neurobiol Dis 139, 104823.

Philipson, O., Hammarström, P., Nilsson, K.P.R., Portelius, E., Olofsson,

T., Ingelsson, M., Hyman, B.T., Blennow, K., Lannfelt, L., Kalimo, H.,

et al. (2009). A highly insoluble state of Aβ similar to that of

Alzheimer’s disease brain is found in Arctic APP transgenic mice.

Neurobiol Aging 30, 1393–1405.

Platt, B., Drever, B., Koss, D., Stoppelkamp, S., Jyoti, A., Plano, A., Utan,

A., Merrick, G., Ryan, D., Melis, V., et al. (2011). Abnormal cognition,

sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse,

PLB1. PLoS ONE 6, e27068.

Plucińska, K., Crouch, B., Koss, D., Robinson, L., Siebrecht, M., Riedel,

G., and Platt, B. (2014). Knock-in of human BACE1 cleaves murine

APP and reiterates Alzheimer-like phenotypes. J Neurosci 34, 10710–

10728.

Poirier, R., Veltman, I., Pflimlin, M.C., Knoflach, F., and Metzger, F.

(2010). Enhanced dentate gyrus synaptic plasticity but reduced

neurogenesis in a mouse model of amyloidosis. Neurobiol Dis 40,

386–393.

Price, K.A., Varghese, M., Sowa, A., Yuk, F., Brautigam, H., Ehrlich, M.E.,

and Dickstein, D.L. (2014). Altered synaptic structure in the

hippocampus in a mouse model of Alzheimer’s disease with soluble

amyloid-β oligomers and no plaque pathology. Mol Neurodegener 9,

41.

Prüßing, K., Voigt, A., and Schulz, J.B. (2013). Drosophila melanogaster as

a model organism for Alzheimer’s disease. Mol Neurodegener 8, 35.

Puig, B., Gómez-Isla, T., Ribé, E., Cuadrado, M., Torrejón-Escribano, B.,

Dalfó, E., and Ferrer, I. (2004). Expression of stress-activated kinases c-

Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau

hyperphosphorylation in neurites surrounding βA plaques in APP

Tg2576 mice. Neuropathol Appl Neurobiol 30, 491–502.

Puoliväli, J., Wang, J., Heikkinen, T., Heikkilä, M., Tapiola, T., van Groen,

T., and Tanila, H. (2002). Hippocampal Aβ42 levels correlate with

spatial memory deficit in APP and PS1 double transgenic mice.

Neurobiol Dis 9, 339–347.

Qiu, Q., Jia, L., Wang, Q., Zhao, L., Jin, H., Li, T., Quan, M., Xu, L., Li, B.,

Li, Y., et al. (2020). Identification of a novel PSEN1 Gly111Val

missense mutation in a Chinese pedigree with early-onset Alzheimer’s

disease. Neurobiol Aging 85, 155.e1–155.e4.

Qu, C., Li, Q.P., Su, Z.R., Ip, S.P., Yuan, Q.J., Xie, Y.L., Xu, Q.Q., Yang,

W., Huang, Y.F., Xian, Y.F., et al. (2022). Nano-Honokiol ameliorates

the cognitive deficits in TgCRND8 mice of Alzheimer’s disease via

inhibiting neuropathology and modulating gut microbiota. J Adv Res

35, 231–243.

Quan, M., Zhao, T., Tang, Y., Luo, P., Wang, W., Qin, Q., Li, T., Wang, Q.,

Fang, J., and Jia, J. (2020). Effects of gene mutation and disease

progression on representative neural circuits in familial Alzheimer’s

disease. Alzheimers Res Ther 12, 14.

Radde, R., Bolmont, T., Kaeser, S.A., Coomaraswamy, J., Lindau, D.,

Stoltze, L., Calhoun, M.E., Jäggi, F., Wolburg, H., Gengler, S., et al.

(2006). Aβ42-driven cerebral amyloidosis in transgenic mice reveals

early and robust pathology. EMBO Rep 7, 940–946.

Ramsden, M., Kotilinek, L., Forster, C., Paulson, J., McGowan, E.,

SantaCruz, K., Guimaraes, A., Yue, M., Lewis, J., Carlson, G., et al.

(2005). Age-dependent neurofibrillary tangle formation, neuron loss,

and memory impairment in a mouse model of human tauopathy

(P301L). J Neurosci 25, 10637–10647.

Rao, C.V., and Yamada, H.Y. (2021). How would preclinical Alzheimer’s

disease (AD pathology) occur? An insight from a genomic instability

mouse model. Neural Regen Res 16, 2012–2014.

Reaume, A.G., Howland, D.S., Trusko, S.P., Savage, M.J., Lang, D.M.,

Greenberg, B.D., Siman, R., and Scott, R.W. (1996). Enhanced

amyloidogenic processing of the β-amyloid precursor protein in gene-

targeted mice bearing the Swedish familial Alzheimer’s disease

mutations and a “humanized” Aβ sequence. J Biol Chem 271, 23380–

23388.

Reichwald, J., Danner, S., Wiederhold, K.H., and Staufenbiel, M. (2009).

Expression of complement system components during aging and

amyloid deposition in APP transgenic mice. J Neuroinflammation 6, 35.

Richard, B.C., Kurdakova, A., Baches, S., Bayer, T.A., Weggen, S., and

Wirths, O. (2015). Gene dosage dependent aggravation of the

neurological phenotype in the 5XFAD mouse model of Alzheimer’s

disease. J Alzheimer Dis 45, 1223–1236.

Richards, J.G., Higgins, G.A., Ouagazzal, A.M., Ozmen, L., Kew, J.N.C.,

Bohrmann, B., Malherbe, P., Brockhaus, M., Loetscher, H., Czech, C.,

et al. (2003). PS2APP transgenic mice, coexpressing hPS2mut and

hAPPswe, show age-related cognitive deficits associated with discrete

brain amyloid deposition and inflammation. J Neurosci 23, 8989–9003.

Richardson, J.C., Kendal, C.E., Anderson, R., Priest, F., Gower, E., Soden,

P., Gray, R., Topps, S., Howlett, D.R., Lavender, D., et al. (2003).

40 Li, X., et al. Sci China Life Sci

Ultrastructural and behavioural changes precede amyloid deposition in

a transgenic model of Alzheimer’s disease. Neuroscience 122, 213–228.

Rockenstein, E., Mallory, M., Mante, M., Sisk, A., and Masliaha, E. (2001).

Early formation of mature amyloid-beta protein deposits in a mutant

APP transgenic model depends on levels of Aβ1-42. J Neurosci Res 66,

573–582.

Rockenstein, E., Mante, M., Alford, M., Adame, A., Crews, L., Hashimoto,

M., Esposito, L., Mucke, L., and Masliah, E. (2005). High β-secretase

activity elicits neurodegeneration in transgenic mice despite reductions

in amyloid-β levels. J Biol Chem 280, 32957–32967.

Roder, S., Danober, L., Pozza, M.F., Lingenhoehl, K., Wiederhold, K.H.,

and Olpe, H.R. (2003). Electrophysiological studies on the

hippocampus and prefrontal cortex assessing the effects of

amyloidosis in amyloid precursor protein 23 transgenic mice.

Neuroscience 120, 705–720.

Rönnbäck, A., Sagelius, H., Bergstedt, K.D., Näslund, J., Westermark, G.

T., Winblad, B., and Graff, C. (2012). Amyloid neuropathology in the

single Arctic APP transgenic model affects interconnected brain

regions. Neurobiol Aging 33, 831.e11–831.e19.

Rupp, N.J., Wegenast-Braun, B.M., Radde, R., Calhoun, M.E., and Jucker,

M. (2011). Early onset amyloid lesions lead to severe neuritic

abnormalities and local, but not global neuron loss in APPPS1

transgenic mice. Neurobiol Aging 32, 2324.e1–2324.e6.

Sadowski, M., Pankiewicz, J., Scholtzova, H., Ji, Y., Quartermain, D.,

Jensen, C.H., Duff, K., Nixon, R.A., Gruen, R.J., and Wisniewski, T.

(2004). Amyloid-β deposition is associated with decreased hippocampal

glucose metabolism and spatial memory impairment in APP/PS1 mice.

J Neuropathol Exp Neurol 63, 418–428.

Saganich, M.J., Schroeder, B.E., Galvan, V., Bredesen, D.E., Koo, E.H.,

and Heinemann, S.F. (2006). Deficits in synaptic transmission and

learning in amyloid precursor protein (APP) transgenic mice require C-

terminal cleavage of APP. J Neurosci 26, 13428–13436.

Sagare, A.P., Bell, R.D., Zhao, Z., Ma, Q., Winkler, E.A., Ramanathan, A.,

and Zlokovic, B.V. (2013). Pericyte loss influences Alzheimer-like

neurodegeneration in mice. Nat Commun 4, 2932.

Saito, S., Yamamoto, Y., Maki, T., Hattori, Y., Ito, H., Mizuno, K., Harada-

Shiba, M., Kalaria, R.N., Fukushima, M., Takahashi, R., et al. (2017).

Taxifolin inhibits amyloid-β oligomer formation and fully restores

vascular integrity and memory in cerebral amyloid angiopathy. Acta

Neuropathol Commun 5, 26.

Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata,

N., and Saido, T.C. (2014). Single App knock-in mouse models of

Alzheimer’s disease. Nat Neurosci 17, 661–663.

Saito, T., Mihira, N., Matsuba, Y., Sasaguri, H., Hashimoto, S.,

Narasimhan, S., Zhang, B., Murayama, S., Higuchi, M., Lee, V.M.Y.,

et al. (2019). Humanization of the entire murine Mapt gene provides a

murine model of pathological human tau propagation. J Biol Chem 294,

12754–12765.

Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira,

N., Matsuba, Y., Yamada, K., Nilsson, P., Takano, J., et al. (2011).

Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci 14,

1023–1032.

Sanchez-Varo, R., Mejias-Ortega, M., Fernandez-Valenzuela, J.J., Nuñez-

Diaz, C., Caceres-Palomo, L., Vegas-Gomez, L., Sanchez-Mejias, E.,

Trujillo-Estrada, L., Garcia-Leon, J.A., Moreno-Gonzalez, I., et al.

(2022). Transgenic mouse models of Alzheimer’s disease: an integrative

analysis. Int J Mol Sci 23, 5404.

SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson,

M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., et al.

(2005). Tau suppression in a neurodegenerative mouse model improves

memory function. Science 309, 476–481.

Sasaguri, H., Hashimoto, S., Watamura, N., Sato, K., Takamura, R., Nagata,

K., Tsubuki, S., Ohshima, T., Yoshiki, A., Sato, K., et al. (2022). Recent

advances in the modeling of Alzheimer’s disease. Front Neurosci 16,

807473.

Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper,

B., Hardy, J., Vassar, R., Winblad, B., and Saido, T.C. (2017). APP mouse

models for Alzheimer’s disease preclinical studies. EMBO J 36, 2473–

2487.

Sato, K., Watamura, N., Fujioka, R., Mihira, N., Sekiguchi, M., Nagata, K.,

Ohshima, T., Saito, T., Saido, T.C., and Sasaguri, H. (2021). A third-

generation mouse model of Alzheimer’s disease shows early and

increased cored plaque pathology composed of wild-type human

amyloid β peptide. J Biol Chem 297, 101004.

Savonenko, A., Xu, G.M., Melnikova, T., Morton, J.L., Gonzales, V.,

Wong, M.P.F., Price, D.L., Tang, F., Markowska, A.L., and Borchelt, D.

R. (2005). Episodic-like memory deficits in the APPswe/PS1dE9 mouse

model of Alzheimer’s disease: Relationships to β-amyloid deposition

and neurotransmitter abnormalities. Neurobiol Dis 18, 602–617.

Savonenko, A.V., Xu, G.M., Price, D.L., Borchelt, D.R., and Markowska,

A.L. (2003). Normal cognitive behavior in two distinct congenic lines

of transgenic mice hyperexpressing mutant APPSWE.Neurobiol Dis 12,

194–211.

Scattoni, M.L., Gasparini, L., Alleva, E., Goedert, M., Calamandrei, G.,

and Spillantini, M.G. (2010). Early behavioural markers of disease in

P301S tau transgenic mice. Behav Brain Res 208, 250–257.

Scearce-Levie, K., Sanchez, P.E., and Lewcock, J.W. (2020). Leveraging

preclinical models for the development of Alzheimer disease

therapeutics. Nat Rev Drug Discov 19, 447–462.

Schneider, I., Reversé, D., Dewachter, I., Ris, L., Caluwaerts, N., Kuipéri,

C., Gilis, M., Geerts, H., Kretzschmar, H., Godaux, E., et al. (2001).

Mutant presenilins disturb neuronal calcium homeostasis in the brain of

transgenic mice, decreasing the threshold for excitotoxicity and

facilitating long-term potentiation. J Biol Chem 276, 11539–11544.

Sebollela, A., Cline, E.N., Popova, I., Luo, K., Sun, X., Ahn, J., Barcelos,

M.A., Bezerra, V.N., Lyra e Silva, N.M., Patel, J., et al. (2017). A

human scFv antibody that targets and neutralizes high molecular weight

pathogenic amyloid-β oligomers. J Neurochem 142, 934–947.

Sehar, U., Rawat, P., Reddy, A.P., Kopel, J., and Reddy, P.H. (2022).

Amyloid beta in aging and Alzheimer’s disease. Int J Mol Sci 23,

12924.

Selkoe, D.J., and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s

disease at 25 years. EMBO Mol Med 8, 595–608.

Serneels, L., Van Biervliet, J., Craessaerts, K., Dejaegere, T., Horré, K., Van

Houtvin, T., Esselmann, H., Paul, S., Schäfer, M.K., Berezovska, O., et

al. (2009). γ-Secretase heterogeneity in the Aph1 subunit: relevance for

Alzheimer’s disease. Science 324, 639–642.

Sevigny, J., Chiao, P., Bussière, T., Weinreb, P.H., Williams, L., Maier, M.,

Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016). The antibody

aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537,

50–56.

Shen, B., Zhang, J., Wu, H., Wang, J., Ma, K., Li, Z., Zhang, X., Zhang, P.,

and Huang, X. (2013). Generation of gene-modified mice via Cas9/

RNA-mediated gene targeting. Cell Res 23, 720–723.

Shen, L., Qin, W., Wu, L., Zhou, A., Tang, Y., Wang, Q., Jia, L., and Jia, J.

(2019). Two novel presenilin-1 mutations (I249L and P433S) in early

onset Chinese Alzheimer’s pedigrees and their functional

characterization. Biochem Biophys Res Commun 516, 264–269.

Shimojo, M., Sahara, N., Mizoroki, T., Funamoto, S., Morishima-

Kawashima, M., Kudo, T., Takeda, M., Ihara, Y., Ichinose, H., and

Takashima, A. (2008). Enzymatic characteristics of I213T mutant

presenilin-1/γ-secretase in cell models and knock-in mouse brains. J

Biol Chem 283, 16488–16496.

Sierksma, A., Escott-Price, V., and De Strooper, B. (2020). Translating

genetic risk of Alzheimer’s disease into mechanistic insight and drug

targets. Science 370, 61–66.

Skaaraas, G.H.E.S., Melbye, C., Puchades, M.A., Leung, D.S.Y., Jacobsen,

Ø., Rao, S.B., Ottersen, O.P., Leergaard, T.B., and Torp, R. (2021).

Cerebral amyloid angiopathy in a mouse model of Alzheimer’s disease

associates with upregulated angiopoietin and downregulated hypoxia-

inducible factor. J Alzheimer Dis 83, 1651–1663.

Snellman, A., López-Picón, F.R., Rokka, J., Salmona, M., Forloni, G.,

Scheinin, M., Solin, O., Rinne, J.O., and Haaparanta-Solin, M. (2013).

Longitudinal amyloid imaging in mouse brain with 11C-PIB:

Li, X., et al. Sci China Life Sci

comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of

Alzheimer disease. J Nucl Med 54, 1434–1441.

Song, W.M., Joshita, S., Zhou, Y., Ulland, T.K., Gilfillan, S., and Colonna,

M. (2018). Humanized TREM2 mice reveal microglia-intrinsic and

-extrinsic effects of R47H polymorphism. J Exp Med 215, 745–760.

Soriano, P. (1999). Generalized lacZ expression with the ROSA26 Cre

reporter strain. Nat Genet 21, 70–71.

Spires, T.L., Orne, J.D., SantaCruz, K., Pitstick, R., Carlson, G.A., Ashe, K.

H., and Hyman, B.T. (2006). Region-specific dissociation of neuronal

loss and neurofibrillary pathology in a mouse model of tauopathy. Am J

Pathol 168, 1598–1607.

Stalder, M., Phinney, A., Probst, A., Sommer, B., Staufenbiel, M., and

Jucker, M. (1999). Association of microglia with amyloid plaques in

brains of APP23 transgenic mice. Am J Pathol 154, 1673–1684.

Stover, K.R., Campbell, M.A., Van Winssen, C.M., and Brown, R.E.

(2015). Early detection of cognitive deficits in the 3xTg-AD mouse

model of Alzheimer’s disease. Behav Brain Res 289, 29–38.

Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.H., Mistl,

C., Rothacher, S., Ledermann, B., Bürki, K., Frey, P., Paganetti, P.A., et

al. (1997). Two amyloid precursor protein transgenic mouse models

with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94,

13287–13292.

Sun, B., Chen, Y., Fan, D., Zhu, C., Zeng, F., and Wang, Y. (2021). Critical

thinking on amyloid-beta-targeted therapy: challenges and perspectives.

Sci China Life Sci 64, 926–937.

Sun, Z.Q., Liu, J.F., Luo, W., Wong, C.H., So, K.F., Hu, Y., and Chiu, K.

(2022). Lycium barbarum extract promotes M2 polarization and reduces

oligomeric amyloid-β-induced inflammatory reactions in microglial

cells. Neural Regen Res 17, 203–209.

Swanson, C.J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R.Y.K.,

Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., et al. (2021). A

randomized, double-blind, phase 2b proof-of-concept clinical trial in

early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril

antibody. Alzheimers Res Ther 13, 80.

Sydow, A., Hochgräfe, K., Könen, S., Cadinu, D., Matenia, D., Petrova, O.,

Joseph, M., Dennissen, F.J., and Mandelkow, E.M. (2016). Age-

dependent neuroinflammation and cognitive decline in a novel

Ala152Thr-Tau transgenic mouse model of PSP and AD. Acta

Neuropathol Commun 4, 17.

Sydow, A., Van der Jeugd, A., Zheng, F., Ahmed, T., Balschun, D., Petrova,

O., Drexler, D., Zhou, L., Rune, G., Mandelkow, E., et al. (2011). Tau-

induced defects in synaptic plasticity, learning, and memory are

reversible in transgenic mice after switching off the toxic Tau mutant.

J Neurosci 31, 2511–2525.

Takahashi, R.H., Almeida, C.G., Kearney, P.F., Yu, F., Lin, M.T., Milner, T.

A., and Gouras, G.K. (2004). Oligomerization of Alzheimer’s β-

amyloid within processes and synapses of cultured neurons and brain. J

Neurosci 24, 3592–3599.

Takeuchi, H., Iba, M., Inoue, H., Higuchi, M., Takao, K., Tsukita, K.,

Karatsu, Y., Iwamoto, Y., Miyakawa, T., Suhara, T., et al. (2011). P301S

mutant human tau transgenic mice manifest early symptoms of human

tauopathies with dementia and altered sensorimotor gating. PLoS ONE

6, e21050.

Tanemura, K., Akagi, T., Murayama, M., Kikuchi, N., Murayama, O.,

Hashikawa, T., Yoshiike, Y., Park, J.M., Matsuda, K., Nakao, S., et al.

(2001). Formation of filamentous tau aggregations in transgenic mice

expressing V337M human tau. Neurobiol Dis 8, 1036–1045.

Tanemura, K., Chui, D.H., Fukuda, T., Murayama, M., Park, J.M., Akagi,

T., Tatebayashi, Y., Miyasaka, T., Kimura, T., Hashikawa, T., et al.

(2006). Formation of tau inclusions in knock-in mice with familial

Alzheimer disease (FAD) mutation of presenilin 1 (PS1). J Biol Chem

281, 5037–5041.

Tanemura, K., Murayama, M., Akagi, T., Hashikawa, T., Tominaga, T.,

Ichikawa, M., Yamaguchi, H., and Takashima, A. (2002).

Neurodegeneration with tau accumulation in a transgenic mouse

expressing V337M human tau. J Neurosci 22, 133–141.

Tatebayashi, Y., Miyasaka, T., Chui, D.H., Akagi, T., Mishima, K., Iwasaki,

K., Fujiwara, M., Tanemura, K., Murayama, M., Ishiguro, K., et al.

(2002). Tau filament formation and associative memory deficit in aged

mice expressing mutant (R406W) human tau. Proc Natl Acad Sci USA

99, 13896–13901.

Terwel, D., Lasrado, R., Snauwaert, J., Vandeweert, E., Van Haesendonck,

C., Borghgraef, P., and Van Leuven, F. (2005). Changed conformation

of mutant Tau-P301L underlies the moribund tauopathy, absent in

progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J

Biol Chem 280, 3963–3973.

Thomas, K.R., and Capecchi, M.R. (1987). Site-directed mutagenesis by

gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512.

Tian, Y., Wang, W., Xu, L., Li, H., Wei, Y., Wu, Q., and Jia, J. (2019).

Activation of Nrf2/ARE pathway alleviates the cognitive deficits in

PS1V97L-Tg mouse model of Alzheimer’s disease through modulation

of oxidative stress. J Neurosci Res 97, 492–505.

Tomiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi,

K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., et al. (2010).

A mouse model of amyloid β oligomers: their contribution to synaptic

alteration, abnormal tau phosphorylation, glial activation, and neuronal

loss in vivo.J Neurosci 30, 4845–4856.

Tomiyama, T., Nagata, T., Shimada, H., Teraoka, R., Fukushima, A.,

Kanemitsu, H., Takuma, H., Kuwano, R., Imagawa, M., Ataka, S., et al.

(2008). A new amyloid β variant favoring oligomerization in

Alzheimer’s-type dementia. Ann Neurol 63, 377–387.

Tomiyama, T., and Shimada, H. (2020). APP Osaka mutation in familial

Alzheimer’s disease—its discovery, phenotypes, and mechanism of

recessive inheritance. Int J Mol Sci 21, 1413.

Tucker, S., Möller, C., Tegerstedt, K., Lord, A., Laudon, H., Sjödahl, J.,

Söderberg, L., Spens, E., Sahlin, C., Waara, E.R., et al. (2015). The

murine version of BAN2401 (mAb158) selectively reduces amyloid-β

protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J

Alzheimer Dis 43, 575–588.

Umeda, T., Kimura, T., Yoshida, K., Takao, K., Fujita, Y., Matsuyama, S.,

Sakai, A., Yamashita, M., Yamashita, Y., Ohnishi, K., et al. (2017).

Mutation-induced loss of APP function causes GABAergic depletion in

recessive familial Alzheimer’s disease: analysis of Osaka mutation-

knockin mice. Acta Neuropathol Commun 5, 59.

Umeda, T., Maekawa, S., Kimura, T., Takashima, A., Tomiyama, T., and

Mori, H. (2014). Neurofibrillary tangle formation by introducing wild-

type human tau into APP transgenic mice. Acta Neuropathol 127, 685–

698.

Umeda, T., Tomiyama, T., Sakama, N., Tanaka, S., Lambert, M.P., Klein,

W.L., and Mori, H. (2011). Intraneuronal amyloid β oligomers cause

cell death via endoplasmic reticulum stress, endosomal/lysosomal

leakage, and mitochondrial dysfunction in vivo.J Neurosci Res 89,

1031–1042.

Van Dam, D., D’Hooge, R., Staufenbiel, M., Van Ginneken, C., Van Meir,

F., and De Deyn, P.P. (2003). Age-dependent cognitive decline in the

APP23 model precedes amyloid deposition. Eur J Neurosci 17, 388–

396.

Van der Jeugd, A., Hochgräfe, K., Ahmed, T., Decker, J.M., Sydow, A.,

Hofmann, A., Wu, D., Messing, L., Balschun, D., D’Hooge, R., et al.

(2012). Cognitive defects are reversible in inducible mice expressing

pro-aggregant full-length human Tau. Acta Neuropathol 123, 787–805.

Van Dorpe, J., Smeijers, L., Dewachter, I., Nuyens, D., Spittaels, K., Van

den Haute, C., Mercken, M., Moechars, D., Laenen, I., Kuiperi, C., et

al. (2000). Prominent cerebral amyloid angiopathy in transgenic mice

overexpressing the london mutant of human APP in neurons. Am J

Pathol 157, 1283–1298.

van Dyck, C.H., Swanson, C.J., Aisen, P., Bateman, R.J., Chen, C., Gee,

M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023).

Lecanemab in early Alzheimer’s disease. N Engl J Med 388, 9–21.

van Ham, T.J., Breitling, R., Swertz, M.A., and Nollen, E.A.A. (2009).

Neurodegenerative diseases: Lessons from genome-wide screens in

small model organisms. EMBO Mol Med 1, 360–370.

Van Skike, C.E., Hussong, S.A., Hernandez, S.F., Banh, A.Q., DeRosa, N.,

and Galvan, V. (2021). mTOR attenuation with rapamycin reverses

42 Li, X., et al. Sci China Life Sci

neurovascular uncoupling and memory deficits in mice modeling

Alzheimer’s disease. J Neurosci 41, 4305–4320.

Veitch, D.P., Weiner, M.W., Aisen, P.S., Beckett, L.A., Cairns, N.J., Green,

R.C., Harvey, D., Jack Jr., C.R., Jagust, W., Morris, J.C., et al. (2019).

Understanding disease progression and improving Alzheimer’s disease

clinical trials: recent highlights from the Alzheimer’s Disease

Neuroimaging Initiative. Alzheimers Dement 15, 106–152.

Vitale, F., Ortolan, J., Volpe, B.T., Marambaud, P., Giliberto, L., and

d’Abramo, C. (2020). Intramuscular injection of vectorized-scFvMC1

reduces pathological tau in two different tau transgenic models. Acta

Neuropathol Commun 8, 126.

Volianskis, A., Køstner, R., Mølgaard, M., Hass, S., and Jensen, M.S.

(2010). Episodic memory deficits are not related to altered

glutamatergic synaptic transmission and plasticity in the CA1

hippocampus of the APPswe/PS1ΔE9-deleted transgenic mice model

of β-amyloidosis. Neurobiol Aging 31, 1173–1187.

Wang, H., Xu, X.X., Pan, Y.C., Yan, Y.X., Hu, X.Y., Chen, R.W., Ravoo, B.

J., Guo, D.S., and Zhang, T. (2021a). Recognition and removal of

amyloid-β by a heteromultivalent macrocyclic coassembly: a potential

strategy for the treatment of Alzheimer’s disease. Adv Mater 33,

2006483.

Wang, J., Guo, X., Lu, W., Liu, J., Zhang, H., Quan, Q., Su, H., Ma, L.,

Gao, F., and Qu, Q. (2021b). Donepezil combined with DL-3-n-

butylphthalide delays cognitive decline in patients with mild to

moderate Alzheimer’s disease: a multicenter, prospective cohort

study. J Alzheimer Dis 80, 673–681.

Wang, J., Tanila, H., Puoliväli, J., Kadish, I., and Groen, T. (2003). Gender

differences in the amount and deposition of amyloidβ in APPswe and

PS1 double transgenic mice. Neurobiol Dis 14, 318–327.

Wang, R., Dineley, K.T., Sweatt, J.D., and Zheng, H. (2004). Presenilin 1

familial Alzheimer’s disease mutation leads to defective associative

learning and impaired adult neurogenesis. Neuroscience 126, 305–312.

Wang, W., Lu, L., Wu, Q., and Jia, J. (2016). Brain amyloid-β plays an

initiating role in the pathophysiological process of the PS1V97L-Tg

mouse model of Alzheimer’s disease. J Alzheimer Dis 52, 1089–1099.

Wang, W., Wei, C., Quan, M., Li, T., and Jia, J. (2020). Sulforaphane

reverses the amyloid-β oligomers induced depressive-like behavior. J

Alzheimer Dis 78, 127–137.

Wang, W.Z., Li, M.W., Chen, Y., Liu, L.Y., Xu, Y., Xia, Z.H., Yu, Y., Wang,

X.D., Chen, W., Zhang, F., et al. (2021c). 3xTg-AD mice over-

expressing phospholipid transfer protein improves cognition through

decreasing amyloid-beta production and tau hyperphosphorylation. J

Alzheimers Dis 82, 1635–1649.

Wang, X., Sun, G., Feng, T., Zhang, J., Huang, X., Wang, T., Xie, Z., Chu,

X., Yang, J., Wang, H., et al. (2019). Sodium oligomannate

therapeutically remodels gut microbiota and suppresses gut bacterial

amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease

progression. Cell Res 29, 787–803.

Wang, Y., Cella, M., Mallinson, K., Ulrich, J.D., Young, K.L., Robinette,

M.L., Gilfillan, S., Krishnan, G.M., Sudhakar, S., Zinselmeyer, B.H., et

al. (2015). TREM2 lipid sensing sustains the microglial response in an

Alzheimer’s disease model. Cell 160, 1061–1071.

Wang, Y., Cheng, Z., Qin, W., and Jia, J. (2012). Val97Leu mutant

presenilin-1 induces tau hyperphosphorylation and spatial memory

deficit in mice and the underlying mechanisms. J Neurochem 121, 135–

145.

Watamura, N., Sato, K., and Saido, T.C. (2022a). Mouse models of

Alzheimer’s disease for preclinical research. Neurochem Int 158,

105361.

Watamura, N., Sato, K., Shiihashi, G., Iwasaki, A., Kamano, N., Takahashi,

M., Sekiguchi, M., Mihira, N., Fujioka, R., Nagata, K., et al. (2022b).

An isogenic panel of App knock-in mouse models: Profiling β-secretase

inhibition and endosomal abnormalities. Sci Adv 8, eabm6155.

Weidensteiner, C., Metzger, F., Bohrmann, A.B.B., Kuennecke, B., and von

Kienlin, M. (2009). Cortical hypoperfusion in the B6.PS2APP mouse

model for Alzheimer’s disease: Comprehensive phenotyping of vascular

and tissular parameters by MRI. Magn Reson Med 62, 35–45.

Wen, P.H., Hof, P.R., Chen, X., Gluck, K., Austin, G., Younkin, S.G.,

Younkin, L.H., DeGasperi, R., Gama Sosa, M.A., Robakis, N.K., et al.

(2004). The presenilin-1 familial Alzheimer disease mutant P117L

impairs neurogenesis in the hippocampus of adult mice. Exp Neurol

188, 224–237.

Wen, P.H., Shao, X., Shao, Z., Hof, P.R., Wisniewski, T., Kelley, K.,

Friedrich Jr., V.L., Ho, L., Pasinetti, G.M., Shioi, J., et al. (2002).

Overexpression of wild type but not an FAD mutant presenilin-1

promotes neurogenesis in the hippocampus of adult mice. Neurobiol

Dis 10, 8–19.

Wilcock, D.M., Lewis, M.R., Van Nostrand, W.E., Davis, J., Previti, M.L.,

Gharkholonarehe, N., Vitek, M.P., and Colton, C.A. (2008). Progression

of amyloid pathology to Alzheimer’s disease pathology in an amyloid

precursor protein transgenic mouse model by removal of nitric oxide

synthase 2. J Neurosci 28, 1537–1545.

Wilhelmus, M.M.M., Chouchane, O., Loos, M., Jongenelen, C.A.M.,

Brevé, J.J.P., Jonker, A., Bol, J.G.J.M., Smit, A.B., and Drukarch, B.

(2022). Absence of tissue transglutaminase reduces amyloid-beta

pathology in APP23 mice. Neuropathol Appl Neurobio 48, e12796.

Williams, T., Ruiz, A.J., Ruiz, A.M., Vo, Q., Tsering, W., Xu, G.,

McFarland, K., Giasson, B.I., Sullivan, P., Borchelt, D.R., et al. (2022).

Impact of APOE genotype on prion-type propagation of tauopathy. Acta

Neuropathol Commun 10, 57.

Willuweit, A., Velden, J., Godemann, R., Manook, A., Jetzek, F., Tintrup,

H., Kauselmann, G., Zevnik, B., Henriksen, G., Drzezga, A., et al.

(2009). Early-onset and robust amyloid pathology in a new

homozygous mouse model of Alzheimer’s disease. PLoS ONE 4,

e7931.

Wirths, O., Erck, C., Martens, H., Harmeier, A., Geumann, C., Jawhar, S.,

Kumar, S., Multhaup, G., Walter, J., Ingelsson, M., et al. (2010).

Identification of low molecular weight pyroglutamate Aβ oligomers in

Alzheimer disease. J Biol Chem 285, 41517–41524.

Wittnam, J.L., Portelius, E., Zetterberg, H., Gustavsson, M.K., Schilling, S.,

Koch, B., Demuth, H.U., Blennow, K., Wirths, O., and Bayer, T.A.

(2012). Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in

transgenic amyloid mouse model for Alzheimer disease. J Biol Chem

287, 8154–8162.

Wong, T.H., Seelaar, H., Melhem, S., Rozemuller, A.J.M., and van Swieten,

J.C. (2020). Genetic screening in early-onset Alzheimer’s disease

identified three novel presenilin mutations. Neurobiol Aging 86, 201.

e9–201.e14.

Wright, A.L., Zinn, R., Hohensinn, B., Konen, L.M., Beynon, S.B., Tan, R.

P., Clark, I.A., Abdipranoto, A., and Vissel, B. (2013).

Neuroinflammation and neuronal loss precede Aβ plaque deposition

in the hAPP-J20 mouse model of Alzheimer’s disease. PLoS ONE 8,

e59586.

Xia, D., Lianoglou, S., Sandmann, T., Calvert, M., Suh, J., Thomsen, E.,

Dugas, J., Pizzo, M., Devos, S., Earr, T., et al. (2021). Fibrillar Aβ

causes profound microglial metabolic perturbations in a novel APP

knock-in mouse model. BioRxiv, 2021.01.19.426731.

Xian, Y.F., Qu, C., Liu, Y., Ip, S.P., Yuan, Q.J., Yang, W., and Lin, Z.X.

(2020). Magnolol ameliorates behavioral impairments and

neuropathology in a transgenic mouse model of Alzheimer’s disease.

Oxid Med Cell Longev 2020, 1–17.

Xiao, N.A., Zhang, J., Zhou, M., Wei, Z., Wu, X.L., Dai, X.M., Zhu, Y.G.,

and Chen, X.C. (2015). Reduction of glucose metabolism in olfactory

bulb is an earlier Alzheimer’s disease-related biomarker in 5XFAD

mice. Chin Med J 128, 2220–2227.

Xie, Z., Meng, J., Kong, W., Wu, Z., Lan, F., Narengaowa, F., Hayashi, Y.,

Yang, Q., Bai, Z., Nakanishi, H., et al. (2022). Microglial cathepsin E

plays a role in neuroinflammation and amyloid β production in

Alzheimer’s disease. Aging Cell 21, e13565.

Xu, F., Grande, A.M., Robinson, J.K., Previti, M.L., Vasek, M., Davis, J.,

and Van Nostrand, W.E. (2007). Early-onset subicular microvascular

amyloid and neuroinflammation correlate with behavioral deficits in

vasculotropic mutant amyloid β-protein precursor transgenic mice.

Neuroscience 146, 98–107.

Li, X., et al. Sci China Life Sci

Xu, H., Rösler, T.W., Carlsson, T., de Andrade, A., Bruch, J., Höllerhage,

M., Oertel, W.H., and Höglinger, G.U. (2014). Memory deficits

correlate with tau and spine pathology in P301S MAPT transgenic

mice. Neuropathol Appl Neurobiol 40, 833–843.

Yamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S.,

Terasaki, T., Hashimoto, T., and Iwatsubo, T. (2009). Aβ

immunotherapy: intracerebral sequestration of Aβ by an anti-Aβ

monoclonal antibody 266 with high affinity to soluble Aβ. J Neurosci

29, 11393–11398.

Yao, Y., Ren, Z., Yang, R., Mei, Y., Dai, Y., Cheng, Q., Xu, C., Xu, X.,

Wang, S., Kim, K.M., et al. (2022). Salidroside reduces neuropathology

in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway. Cell

Biosci 12, 180.

Yi-Bin, W., Xiang, L., Bing, Y., Qi, Z., Fei-Tong, J., Minghong, W.,

Xiangxiang, Z., Le, K., Yan, L., Ping, S., et al. (2022). Inhibition of the

CEBPβ-NFκB interaction by nanocarrier-packaged Carnosic acid

ameliorates glia-mediated neuroinflammation and improves cognitive

function in an Alzheimer’s disease model. Cell Death Dis 13, 318.

Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.M., Iwata, N., Saido, T.

C., Maeda, J., Suhara, T., Trojanowski, J.Q., and Lee, V.M.Y. (2007).

Synapse loss and microglial activation precede tangles in a P301S

tauopathy mouse model. Neuron 53, 337–351.

Youmans, K.L., Tai, L.M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo,

T., Gan, M., Kim, J., Eimer, W.A., Estus, S., Rebeck, G.W., et al.

(2012). APOE4-specific changes in Aβ accumulation in a new

transgenic mouse model of Alzheimer disease. J Biol Chem 287,

41774–41786.

Yu, J.T., Xu, W., Tan, C.C., Andrieu, S., Suckling, J., Evangelou, E., Pan,

A., Zhang, C., Jia, J., Feng, L., et al. (2020). Evidence-based prevention

of Alzheimer’s disease: systematic review and meta-analysis of 243

observational prospective studies and 153 randomised controlled trials.

J Neurol Neurosurg Psychiatry 91, 1201–1209.

Yue, M., Hanna, A., Wilson, J., Roder, H., and Janus, C. (2011). Sex

difference in pathology and memory decline in rTg4510 mouse model

of tauopathy. Neurobiol Aging 32, 590–603.

Zampar, S., and Wirths, O. (2021). Characterization of a mouse model of

Alzheimer’s disease expressing Aβ4-42 and human mutant tau. Int J

Mol Sci 22, 5191.

Zhang, H., Han, T., Zhang, L., Yu, C.H., Wan, D.G., Rahman, K., Qin, L.P.,

and Peng, C. (2008). Effects of tenuifolin extracted from radix

polygalae on learning and memory: a behavioral and biochemical

study on aged and amnesic mice. Phytomedicine 15, 587–594.

Zhang, L., Chen, C., Mak, M.S., Lu, J., Wu, Z., Chen, Q., Han, Y., Li, Y.,

and Pi, R. (2020). Advance of sporadic Alzheimer’s disease animal

models. Med Res Rev 40, 431–458.

Zhang, X., Wei, X., Mei, Y., Wang, D., Wang, J., Zhang, Y., Li, X., Gu, Y.,

Peng, G., and Sun, B. (2021). Modulating adult neurogenesis affects

synaptic plasticity and cognitive functions in mouse models of

Alzheimer’s disease. Stem Cell Rep 16, 3005–3019.

Zhang, Y., Huang, L.J., Shi, S., Xu, S.F., Wang, X.L., and Peng, Y. (2016).

L-3-n-butylphthalide rescues hippocampal synaptic failure and

attenuates neuropathology in aged APP/PS1 mouse model of

Alzheimer’s disease. CNS Neurosci Ther 22, 979–987.

Zhang, Y., Lu, L., Jia, J., Jia, L., Geula, C., Pei, J., Xu, Z., Qin, W., Liu, R.,

Li, D., et al. (2014). A lifespan observation of a novel mouse model: in

vivo evidence supports Aβ oligomer hypothesis. PLoS ONE 9, e85885.

Zhao, S., Fan, Z., Zhang, X., Li, Z., Shen, T., Li, K., Yan, Y., Yuan, Y., Pu,

J., Tian, J., et al. (2023). Metformin attenuates tau pathology in tau-

seeded PS19 mice. Neurotherapeutics 20, 452–463.

Zhong, W., Wu, A., Berglund, K., Gu, X., Jiang, M.Q., Talati, J., Zhao, J.,

Wei, L., and Yu, S.P. (2022). Pathogenesis of sporadic Alzheimer’s

disease by deficiency of NMDA receptor subunit GluN3A. Alzheimers

Dement 18, 222–239.

Zou, C., Montagna, E., Shi, Y., Peters, F., Blazquez-Llorca, L., Shi, S.,

Filser, S., Dorostkar, M.M., and Herms, J. (2015). Intraneuronal APP

and extracellular Aβ independently cause dendritic spine pathology in

transgenic mouse models of Alzheimer’s disease. Acta Neuropathol

129, 909–920.

Zufferey, V., Vallet, P.G., Moeri, M., Moulin-Sallanon, M., Piotton, F.,

Marin, P., and Savioz, A. (2013). Maladaptive exploratory behavior and

neuropathology of the PS-1 P117L Alzheimer transgenic mice. Brain

Res Bull 94, 17–22.

44 Li, X., et al. Sci China Life Sci

DTD1 modulates synaptic efficacy by maintaining D-serine and D-aspartate homeostasis

Article

Oct 2024

D-serine and D-aspartate are involved in N-methyl-D-aspartate receptor (NMDAR)-related physiological and pathological processes. D-aminoacyl-tRNA deacylase 1 (DTD1) may biochemically contribute to D-serine or D-aspartate production. However, it is unclear thus far whether DTD1 regulates D-serine or D-aspartate content in neurobiological processes. In the present research, we found that DTD1 was essential to maintain the D-serine or D-aspartate homeostasis, which was consistent with the phenomenon that DTD1-deficiency resulted in changes in the quantity changes of functional NMDAR subunits in postsynaptic compartments. Moreover, DTD1 played a considerable role in regulating dendritic morphology and synaptic structure. As a consequence, DTD1 affected neurobiological events, including the synaptic strength of the CA3-to-CA1 circuit, dendritic spine density of hippocampal pyramidal neurons, and behavioral performance of mice in the Morris water maze. These findings highlight the important role of DTD1 in synaptic transmission, neuronal morphology, and spatial learning and memory and suggest an undisclosed mechanism of DTD1 that participates the regulation of D-serine or D-aspartate homeostasis in hippocampal neurons.

Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis

Article

Full-text available

Sep 2023
INT J MOL SCI

Ernesto Fedele

Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer’s disease (AD) focused on clearing the β-amyloid peptide (Aβ) from the brain since, according to the amyloid cascade hypothesis, the peptide was (and it is still considered by many) the pathogenic determinant of this neurodegenerative disorder. However, as reviewed in this article, results from the numerous clinical trials that have tested anti-Aβ therapies to date indicate that this peptide plays a minor role in the pathogenesis of AD. Indeed, even Aducanumab and Lecanemab, the two antibodies recently approved by the FDA for AD therapy, as well as Donanemab showed limited efficacy on cognitive parameters in phase III clinical trials, despite their capability of markedly lowering Aβ brain load. Furthermore, preclinical evidence demonstrates that Aβ possesses several physiological functions, including memory formation, suggesting that AD may in part be due to a loss of function of this peptide. Finally, it is generally accepted that AD could be the result of many molecular dysfunctions, and therefore, if we keep chasing only Aβ, it means that we cannot see the forest for the trees.

Beyond Transgenic Mice: Emerging Models and Translational Strategies in Alzheimer’s Disease

Article

Jun 2025
INT J MOL SCI

Alzheimer’s disease (AD) is a leading cause of dementia and a growing public health concern worldwide. Despite decades of research, effective disease-modifying treatments remain elusive, partly due to limitations in current experimental models. The purpose of this review is to critically assess and compare existing murine and alternative models of AD to identify key strengths, limitations, and future directions for model development that can enhance translational relevance and therapeutic discovery. Traditional transgenic mouse models have advanced the understanding of amyloid-beta and tau pathologies, but often fail to capture the complexity of sporadic, late-onset AD. In response, alternative models—including zebrafish, Drosophila melanogaster, Caenorhabditis elegans, non-human primates, and human brain organoids—are gaining traction due to their complementary insights and diverse experimental advantages. This review also discusses innovations in genetic engineering, neuroimaging, computational modelling, and drug repurposing that are reshaping the landscape of AD research. By integrating these diverse approaches, the review advocates for a multi-model, multidisciplinary strategy to improve the predictive power, accelerate clinical translation, and inform personalised therapeutic interventions. Ethical considerations and equitable access to diagnostics and emerging treatments are also emphasised. Ultimately, this work aims to support the development of more accurate, effective, and human-relevant models to combat AD.

The Impact of the Exposome on Alzheimer’s Disease: The Influence of Nutrition

Article

Full-text available

Mar 2025
INT J MOL SCI

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory loss, and behavioural changes. While genetic predispositions and pathological processes have been the traditional focus, this review highlights the fundamental role of environmental factors, particularly nutrition, within the exposome framework in modulating the risk and progression of AD. The exposome, which includes the totality of environmental exposures in an individual’s lifetime, provides a comprehensive approach to understanding the complex aetiology of AD. In this review, we explore the impact of dietary factors and cyclic nucleotide pathways (cAMP/cGMP) on AD, emphasizing the potential of dietary interventions as therapeutic strategies. We investigate key aspects of how nutrition affects the accumulation of β-amyloid, the aggregation of tau proteins, and neuroinflammation. We also examine the impact of specific nutrients on cognitive performance and the risk of AD. Additionally, we discuss the potential of nutraceuticals with anti-phosphodiesterase activity and the role of various animal models of AD (such as 5xFAD, 3xTg-AD, Tg2576, and APP/PS1 mice) in demonstrating the effects of dietary interventions on disease onset and progression.

Humanized rodent models of neurodegenerative diseases and other brain disorders

Article

Mar 2025
NEUROSCI BIOBEHAV R

Advancements and challenges in mouse models of Alzheimer’s disease

Article

Nov 2024
TRENDS MOL MED

Timing of biomarker changes preceding Alzheimer's disease: for diagnosis, treatment or prevention?

Article

Full-text available

Oct 2024
Sci China Life Sci

Meina Quan

Blood-brain barrier dysfunction and Alzheimer’s disease: associations, pathogenic mechanisms, and therapeutic potential

Article

Full-text available

Nov 2023

Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ), hyperphosphorylation of tau, and neuroinflammation in the brain. The blood–brain barrier (BBB) limits solutes from circulating blood from entering the brain, which is essential for neuronal functioning. Focusing on BBB function is important for the early detection of AD and in-depth study of AD pathogenic mechanisms. However, the mechanism of BBB alteration in AD is still unclear, which hinders further research on therapeutics that target the BBB to delay the progression of AD. The exact timing of the vascular abnormalities in AD and the complex cause-and-effect relationships remain uncertain. Thus, it is necessary to summarize and emphasize this process. First, in this review, the current evidence for BBB dysfunction in AD is summarized. Then, the interrelationships and pathogenic mechanisms between BBB dysfunction and the risk factors for AD, such as Aβ, tau, neuroinflammation, apolipoprotein E (ApoE) genotype and aging, were analyzed. Finally, we discuss the current status and future directions of therapeutic AD strategies targeting the BBB. We hope that these summaries or reviews will allow readers to better understand the relationship between the BBB and AD.

Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer’s disease

Article

Full-text available

Jun 2023
BMC MED

Background The identification of pathogenic mutations in Alzheimer’s disease (AD) causal genes led to a better understanding of the pathobiology of AD. Familial Alzheimer’s disease (FAD) is known to be associated with mutations in the APP, PSEN1, and PSEN2 genes involved in Aβ production; however, these genetic defects occur in only about 10–20% of FAD cases, and more genes and new mechanism causing FAD remain largely obscure. Methods We performed exome sequencing on family members with a FAD pedigree and identified gene variant ZDHHC21 p.T209S. A ZDHHC21T209S/T209S knock-in mouse model was then generated using CRISPR/Cas9. The Morris water navigation task was then used to examine spatial learning and memory. The involvement of aberrant palmitoylation of FYN tyrosine kinase and APP in AD pathology was evaluated using biochemical methods and immunostaining. Aβ and tau pathophysiology was evaluated using ELISA, biochemical methods, and immunostaining. Field recordings of synaptic long-term potentiation were obtained to examine synaptic plasticity. The density of synapses and dendritic branches was quantified using electron microscopy and Golgi staining. Results We identified a variant (c.999A > T, p.T209S) of ZDHHC21 gene in a Han Chinese family. The proband presented marked cognitive impairment at 55 years of age (Mini-Mental State Examination score = 5, Clinical Dementia Rating = 3). Considerable Aβ retention was observed in the bilateral frontal, parietal, and lateral temporal cortices. The novel heterozygous missense mutation (p.T209S) was detected in all family members with AD and was not present in those unaffected, indicating cosegregation. ZDHHC21T209S/T209S mice exhibited cognitive impairment and synaptic dysfunction, suggesting the strong pathogenicity of the mutation. The ZDHHC21 p.T209S mutation significantly enhanced FYN palmitoylation, causing overactivation of NMDAR2B, inducing increased neuronal sensitivity to excitotoxicity leading to further synaptic dysfunction and neuronal loss. The palmitoylation of APP was also increased in ZDHHC21T209S/T209S mice, possibly contributing to Aβ production. Palmitoyltransferase inhibitors reversed synaptic function impairment. Conclusions ZDHHC21 p.T209S is a novel, candidate causal gene mutation in a Chinese FAD pedigree. Our discoveries strongly suggest that aberrant protein palmitoylation mediated by ZDHHC21 mutations is a new pathogenic mechanism of AD, warranting further investigations for the development of therapeutic interventions.

Current Pharmacotherapy and Multi-Target Approaches for Alzheimer’s Disease

Article

Full-text available

Dec 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by decreased synaptic transmission and cerebral atrophy with appearance of amyloid plaques and neurofibrillary tangles. Cognitive, functional, and behavioral alterations are commonly associated with the disease. Different pathophysiological pathways of AD have been proposed, some of which interact and influence one another. Current treatment for AD mainly involves the use of therapeutic agents to alleviate the symptoms in AD patients. The conventional single-target treatment approaches do not often cause the desired effect in the disease due to its multifactorial origin. Thus, multi-target strategies have since been undertaken, which aim to simultaneously target multiple targets involved in the development of AD. In this review, we provide an overview of the pathogenesis of AD and the current drug therapies for the disease. Additionally, rationales of the multi-target approaches and examples of multi-target drugs with pharmacological actions against AD are also discussed.

Metformin Attenuates Tau Pathology in Tau-Seeded PS19 Mice

Article

Full-text available

Nov 2022

Accumulation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Growing evidence demonstrated that tau pathology in AD spreads in a prion-like manner. Previous studies showed that metformin might have a positive effect on cognition. However, the underlying mechanisms are still unknown. Therefore, the present study aimed to investigate the effects of metformin on tau propagation. Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of PS19 mice. Metformin was administrated through drinking water for four months, and we observed tau spreading in the brain of tau-seeded PS19 mice. Metformin inhibited the spreading of tau pathology in the ipsilateral hemisphere, attenuated tau pathology in the contralateral hemisphere, and reduced the hyperphosphorylation of tau at Ser202/Thr205, Thr231, and Ser422 sites in the soluble fraction and Ser202/Thr205, Ser262, Thr396, Thr231, and Ser422 sites in the insoluble fraction of tau-seeded PS19 mice brains. Metformin did not affect tau kinases or phosphatase 2A protein levels but reduced mTORC1 protein levels. Additionally, metformin reduced learning and memory deficits of the tau-seeded PS19 mice. These findings indicate that metformin reduced tau hyperphosphorylation, attenuated tau pathology in tau-seeded PS19 mice, and improved learning and memory deficits. These findings highlight the potential mechanisms underlying the beneficial effects of metformin on cognition, implying that metformin could be a promising drug for the prevention and early treatment of AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-022-01316-6.

Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway

Article

Full-text available

Nov 2022

Background Neurite dystrophy is a pathologic hallmark of Alzheimer’s disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Methods Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. Results SAL ameliorates Aβ-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aβ pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. Conclusions Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD.

Amyloid Beta in Aging and Alzheimer’s Disease

Article

Full-text available

Oct 2022
INT J MOL SCI

Alzheimer’s disease (AD), is a progressive neurodegenerative disease that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs in two forms, early onset familial and late-onset sporadic; genetic mutations in PS1, PS2, and APP genes cause early onset familial AD, and a combination of lifestyle, environment and genetic factors causes the late-onset sporadic form of the disease. However, accelerated disease progression is noticed in patients with familial AD. Disease-causing pathological changes are synaptic damage, and mitochondrial structural and functional changes, in addition to increased production and accumulation of phosphorylated tau (p-tau), and amyloid beta (Aβ) in the affected brain regions in AD patients. Aβ is a peptide derived from amyloid precursor protein (APP) by proteolytic cleavage of beta and gamma secretases. APP is a glycoprotein that plays a significant role in maintaining neuronal homeostasis like signaling, neuronal development, and intracellular transport. Aβ is reported to have both protective and toxic effects in neurons. The purpose of our article is to summarize recent developments of Aβ and its association with synapses, mitochondria, microglia, astrocytes, and its interaction with p-tau. Our article also covers the therapeutic strategies that reduce Aβ toxicities in disease progression and discusses the reasons for the failures of Aβ therapeutics.

Carnosic Acid Attenuates AβOs-Induced Apoptosis and Synaptic Impairment via Regulating NMDAR2B and Its Downstream Cascades in SH-SY5Y Cells

Article

Full-text available

Oct 2022
MOL NEUROBIOL

Neuronal death and synaptic loss are principal pathological features of Alzheimer's disease (AD). Amyloid beta oligomers (AβOs) constitute the main neurotoxin underscoring AD pathology. AβOs interact with N-methyl-D-aspartate receptors (NMDARs), resulting in neurotoxic events, including activation of apoptosis and synaptic impairment. Carnosic acid (CA), extracted from Salvia rosmarinus, has been verified its neuroprotective effects in AD. However, the precise mechanisms by which CA induces synaptic protection remain unclear. In this study, we established an in vitro AD model using SH-SY5Y human neuroblastoma cells. We observed that CA improved neuronal survival by suppressing apoptosis. Moreover, CA restored synaptic impairments by increasing expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), and synaptophysin (Syn). Furthermore, we found these protective effects were dependent on inhibiting the phosphorylation of NMDAR subtype 2B (NMDAR2B), which further suppressed calcium overload and promoted activation of the extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB) pathway. Administration of N-methyl-D-aspartic acid (NMDA), an agonist of NMDARs, abolished these effects of CA. Our findings demonstrate that CA exerts neuroprotective effects in an in vitro model of AD by regulating NMDAR2B and its downstream cascades, highlighting the therapeutic potential of CA as a NMDARs-targeted candidate in the treatment of AD.

Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity

Article

Full-text available

Oct 2022

Background Eleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results. Methods We selected two single domain antibodies (sdAbs) derived from a llama immunized with tau proteins and utilized them to generate an array of Fc-(sdAb)2 subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice. Findings Unmodified sdAbs were non-toxic, blocked tau toxicity and promoted tau clearance. However, the efficacy/safety profile of their Fc-(sdAb)2 subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo. Interpretation These findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it. Funding Funding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051).

A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer’s disease mouse model

Article

Full-text available

Aug 2022

Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer’s disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α–neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aβ-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid β deposition and β-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aβ. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aβ-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.

Lecanemab in Early Alzheimer’s Disease

Article

Nov 2022

Background: The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease. Methods: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). Results: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. Conclusions: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

Gene–environment interactions in Alzheimer disease: the emerging role of epigenetics

Article

Sep 2022

With the exception of a few monogenic forms, Alzheimer disease (AD) has a complex aetiology that is likely to involve multiple susceptibility genes and environmental factors. The role of environmental factors is difficult to determine and, until a few years ago, the molecular mechanisms underlying gene-environment (G × E) interactions in AD were largely unknown. Here, we review evidence that has emerged over the past two decades to explain how environmental factors, such as diet, lifestyle, alcohol, smoking and pollutants, might interact with the human genome. In particular, we discuss how various environmental AD risk factors can induce epigenetic modifications of key AD-related genes and pathways and consider how epigenetic mechanisms could contribute to the effects of oxidative stress on AD onset. Studies on early-life exposures are helping to uncover critical time windows of sensitivity to epigenetic influences from environmental factors, thereby laying the foundations for future primary preventative approaches. We conclude that epigenetic modifications need to be considered when assessing G × E interactions in AD.

Critical thinking of Alzheimer's transgenic mouse model: current research and future perspective

Abstract

Recommended publications

A unique transgenic model that expressing Aβ oligomers: PS1V97L mutation discovered from Chinese Alz...

New Treatments for Alzheimer’s Dementia

Single‐nuclei spatiotemporal transcriptomics reveal an APOE4‐associated specific oligodendrocyte sig...

Alzheimer’s disease and immunotherapy