SAGE-Hindawi Access to Research
International Journal of Alzheimer’s Disease
Volume 2010, Article ID 723782, 6 pages
NeuronLoss inTransgenicMouse Models of Alzheimer’sDisease
OliverWirthsand Thomas A.Bayer
Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen,
von-Siebold-Str. 5, 37075 Goettingen, Germany
Correspondence should be addressed to Oliver Wirths, firstname.lastname@example.org
Received 3 May 2010; Revised 5 July 2010; Accepted 9 July 2010
Academic Editor: Gemma Casadesus
Copyright © 2010 O. Wirths and T. A. Bayer. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Since their initial generation in the mid 1990s, transgenic mouse models of Alzheimers’s disease (AD) have been proven to be
valuable model systems which are indispensable for modern AD research. Whereas most of these models are characterized by
extensive amyloid plaque pathology, inflammatory changes and often behavioral deficits, modeling of neuron loss was much less
successful. The present paper discusses the current achievements of modeling neuron loss in transgenic mouse models based on
APP/Aβ and Tau overexpression and provides an overview of currently available AD mouse models showing these pathological
Alzheimer’s disease (AD) represents the most frequent form
of dementia and is characterized by two major neuropatho-
logical hallmarks: (i) extracellular plaques composed of the
40–42 residues Aβ peptide  and (ii) neurofibrillary tangles
(NFTs), consisting of abnormal phosphorylated Tau protein
. There is increasing evidence that, in addition to the well-
known extracellular amyloid deposition in the parenchyma,
Aβ peptides accumulate within neurons . It has been
hypothesized that this initial accumulation is one of the
earliest pathological events, which is able to trigger the
cascade leading to neurodegeneration . Whereas the vast
majority of AD cases occur sporadically, a small percentage
(<2%) of all cases represents familial forms of AD with an
autosomal dominant mode of inheritance. Identification of
generation in the mid 1990s, transgenic mice have been
proven to represent valuable model systems reflecting vari-
ous pathological aspects of AD including plaque deposition,
in [5, 6]). In the present short paper, we summarize the
current achievements of modeling neuron loss in transgenic
mice based on APP/Aβ overexpression.
2.APP-/Aβ-Based Mouse Models with
A variety of different transgenic AD mouse models have
been developed during the last 15 years which can be
categorized as either APP single transgenic mice (e.g., PD-
APP , Tg2576 , APP/Ld , TgCRND8 , APP23
, tg APP ArcSwe , APP-Au , or APPE693Δ),
bigenic mice expressing both APP and PS1/PS2 or Tau
(e.g., APPswe/PS1dE9 , APP/PS1 , PS2APP ,
APP/PS1KI , or APP/tau ), and triple transgenic
mice expressing APP, PS1, and Tau (e.g., 3xTg  or
TauPS2APP ). Whereas most of these models present
abundant extracellular amyloid plaque pathology, several
efforts modelling significant neuron loss remained less
successful [22, 23].
First evidence for neurotoxic in vivo properties of Aβ
came from a transgenic mouse model expressing murine
Aβ under the control of the mouse Neurofilament-light
gene (NF-L) promoter, ensuring neuronal expression. This
resulted in abundant neurodegeneration, with biochemical
and morphological evidence for an apoptotic mechanism
. Later, a transgenic mouse model expressing human
APP with the Swedish mutation (APP23) under the con-
trol of the murine Thy1-promoter was reported, showing
2 International Journal of Alzheimer’s Disease
Figure 1: Hippocampal neuron loss in the APP/PS1KI mouse model of AD. (a) APP (brown) and Aβ staining (green) in the hippocampal
formation of a 2-month-old and (c) a 10-month-old APP/PS1KI mouse. (b,d) Higher magnification of the CA1 granular cell layer of a
2-month-old (b) and a 10-month-old APP/PS1KI reveals profound neuron loss at the later time point. Scale bars: (a,c): 200μm, (b,d):
significant hippocampal CA1 neuron loss (−14%) at the age
of 14 to 18 months. These mice show an age-dependent
extracellular plaque deposition primarily in neocortex and
hippocampus, accompanied by severe gliosis. The number
of CA1 neurons is inversely correlated with CA1 plaque
load and neuron loss was observed primarily in the vicinity
of extracellular plaques . It has been shown that focal
neuronal toxicity is associated with extracellular Aβ deposits
. Surprisingly, no differences in the neocortical synaptic
bouton number as well as in synaptophysin protein levels
were detected during aging or in comparison with age-
matched nontransgenic control mice .
Analysis of 17-month-old APP751SL/PS1M146L trans-
genic mice using unbiased stereologic methods revealed a
loss of CA1-3 neurons in a magnitude of ∼30% compared to
age-matched PS1 control animals. Interestingly, the plaque
load was approximately 10% smaller than the level of
hippocampal pyramidal cell loss in these mice, indicating a
loss of neurons at sites of Aβ aggregation but also clearly
observedinareasdistantfromextracellularAβ deposits. This
observation points to the potential involvement of more
than one mechanism in hippocampal neuron loss in this
mouse model . A quantitative study of synaptophysin-
immunoreactive presynaptic boutons (SIPBs) revealed an
age-related loss in both APP751SL and PS1M146L single
transgenic mice within the stratum radiatum, which was
most severe in APP751SL/PS1M146L mice extending also to
plaque-free regions .
Another model showing a more severe hippocampal
neuron loss is the APP/PS1KI mouse model . At the
age of 10 months an extensive neuron loss (>50%) in
the hippocampus was reported, that correlated with the
accumulation of intraneuronal Aβ and Thioflavin-S positive
to earlier ones revealed that this CA1 neuron loss is already
detectable at the age of 6 months. At this time point,
a loss of 33% of CA1 pyramidal neurons compared to
PS1KI littermates could be demonstrated, together with a
hippocampus of 18% and synaptic alterations, including
reduced levels of pre- (SNAP25, clathrin light chain) and
post-synaptic markers (PSD-95). In addition, recordings of
field excitatory postsynaptic potentials (fEPSPs) revealed a
significant reduction of 6 months in APP/PS1KI compared
to PS1KI or nontransgenic mice . A detailed stereo-
logical comparison of neuronal numbers in frontal cortex
and thalamus, representing brain areas with intra- and
extracellular Aβ accumulation (frontal cortex) or with only
extracellular Aβ pathology (thalamus), revealed an early loss
of cortical neurons starting at the age of 6 months. This
neuronal loss correlated with the transient intraneuronal
International Journal of Alzheimer’s Disease3
Table 1: Overview of transgenic AD mouse models in which neuronal loss and/or intraneuronal Aβ accumulation has been reported. In
addition, information on the transgene, extracellular plaque onset, and intraneuronal Aβ accumulation are given. (n.d.: not determined).
Thy1 (APP) PS1
Thy1 (APP, PS1)2m
Thy1 (APP, Tau)
(APP) Thy1 (Tau)
Thy1 (APP, PS2,
9mn.d.9m n.d. 
TauPS2APPSwedish N141I (PS2)
4m n.d.— n.d.
Aβ accumulation. No neuron loss could be observed in
the thalamus where on extracellular Aβ plaques, however,
in a comparable amount as in the cortex were present
. A related observation was made in distinct cholinergic
brain stem nuclei (Mo5, 7N) in this mouse model, where
neuronal loss at 6 or 12 months of age correlated with the
presence of intraneuronal Aβ peptides . Interestingly, a
significant loss of parvalbumin- (PV)-positive interneurons
in CA1-2 (40%–50%) and calretinin- (CR)-immunoreactive
interneurons in the hilus and dentate gyrus (37%–52%) has
been recently reported in 10-month-old APP/PS1KI mice
. This is in the range of PV- and CR-positive interneuron
losses in the dentate gyrus of postmortem brain specimen
from AD patients. In addition, a significant neuron loss
has been found in the granule cell layer of the dentate
gyrus of 12-month-old APP/PS1KI mice, where abundant
Aβ deposition is present. This loss is likely due to local
extracellular plaque pathology , in combination with a
complete loss of neurogenesis already at the age of 6 months
[35, 36], which prevents any re-integration of new-born
neurons in that particular cell layer.
A recently described mouse model expressing mutant
APP and PS1 under the control of the murine Thy1
promoter (5XFAD mice) underscores the potential influence
of intraneuronal Aβ accumulation on the loss of neurons.
Analysis of cresyl violet stained sections in 9-month-old
mice revealed a reduced number of cortical layer 5 neurons,
a region with robust intracellular Aβ immunoreactivity.
The same holds true for the subiculum where neurons
where pale or entirely missing . In a very recent report,
cortical and hippocampal neuron numbers were analysed by
design-based unbiased stereological methods in 12-month-
old female mice, verifying the discrete layer 5 neuron loss.
No reductions in neuron numbers and no intraneuronal
Aβ immunoreactivity were detected in the CA1 layer of the
hippocampus adding further evidence to the assumption
that intraneuronal Aβ accumulation is closely associated
with neuron loss . These mice also show synaptic
already at 4 months of age as well as significantly reduced
syntaxin and PSD-95 levels at the age of 9 months .
Besides full-length Aβ peptides ending at amino acid
40 or 42, N-terminally truncated peptides have recently
gained in importance. One of the most abundant truncated
peptides in AD brain is AβpE3–42carrying a pyroglutamate
(pE) at position 3 . It has been demonstrated that this
peptide is characterized by a higher aggregation propensity
, stability , and increased toxicity compared to full-
length Aβ . Recently in vivo toxicity of this peptide has
been demonstrated in a mouse model expressing AβpE3–42
in neurons under the control of the murine Thy1 promoter.
Glutamate (E) at position three of Aβ has been mutated
into glutamine (Q), as it is well established that glutamine
becomes much faster converted into pyroglutamate. These
mice showed a severe neurological phenotype with prema-
ture death and abundant loss of cerebellar Purkinje cells
Very recently, a new transgenic mouse model express-
ing human APP with the APPE693Δ mutation has been
published . This mutation has been initially described
in a Japanese pedigree showing Alzheimer’s-type dementia
and is characterized by decreased total Aβ secretion but
oligomerization . The resulting transgenic mice dis-
played intraneuronal accumulation of Ab oligomers staring
at the age of 8 months, however, no extracellular Aβ plaque
formation could be detected even at the age of 24 months. In
addition, micro-and astroglial accumulation was observed,
4 International Journal of Alzheimer’s Disease
as well as a significant decrease in the number of NeuN-
positive cells in the hippocampal CA3 region at 24 months of
age compared to age-matched nontransgenic littermates and
transgenic mice expressing wild-type APP. Furthermore, an
age-dependent decrease in synaptophysin levels was shown
by means of immunohistochemistry starting at the age of
8 months, which coincides with impairments in synaptic
plasticity as shown by in vivo electrophysiology  (see
3.APP andTauTransgenic MouseModels
expressing both mutant APP (Swedish) and Tau (P301L) on
a mutant PS1 knockin background (3xTg-AD mice) .
Intracellular Aβ is apparent between 3 and 4 months in
these mice and precedes the deposition of extracellular Aβ
peptides starting around the age of 6 months. At this time
point synaptic plasticity was already strongly compromised
in these mice, as shown by impaired long-term potentiation
accumulation is functionally linked to cognitive impairment
in these mice, as they develop deficits in long-term retention
at the age of 4 months, a time point prior to plaque
deposition where only intracellular Aβ is present .
Morphological alterations of hippocampal synapses have
been characterized in 13-month-old 3xTg-AD mice and
age-matched PS1KI control mice. The numeric density of
synapses, the average synaptic contact area as well as the
synaptic surface density were not altered, however, 3xTg-
AD mice showed a significant reduction in the fraction of
perforated synapses, which is believed to represent a reliable
indirect index of synaptic plasticity .
A double transgenic mouse line based on Tg2576 mice
increased amyloid deposition at the age of 16 months com-
pared to APP single transgenic mice. In addition, APP/Tau
mice revealed a significantly reduced neuron number in the
entorhinal cortex at 9 months of age compared to APP single
transgenic, Tau single transgenic, or wild-type mice, which
were extended to the CA1 layer at the age of 16 months.
It was further reported that cell death in these APP/Tau
mice preceded overt amyloid plaque formation and NFT
formation and did not correlate with amyloid burden in any
of the regions examined .
Another new transgenic mouse line expressing mutant
APP, Presenilin-2 (PS2), and Tau (TauPs2APP) has been
recently described. It has been demonstrated that Aβ in
these triple transgenic mice impacts on Tau pathology by
increasing the phosphorylation of Tau at serine 422. How-
ever, despite of increased levels of phosphorylated Tau, no
subregions comparing triple transgenic and wild-type mice.
Quantitative receptor autoradiography revealed significantly
reduced mGluR2 levels in aged triple transgenic mice,
which were however not different from the PS2APP double
transgenic control line, arguing against a prominent role of
increased Tau phosphorylation .
In summary, there is no doubt that transgenic mice have
been proven to be valuable model systems in modern AD
research. There is accumulating evidence that significant
neuron loss in APP/Aβ-related transgenic mice is linked to
intraneuronal Aβ accumulation, as this pathological alter-
ation precedes neurodegeneration in almost all the models
where neuronal loss has been convincingly reported. If this
is also true for the human situation is currently less clear, as
might not be adequately detected in end-stage AD patients.
Although it has been shown that reductions in Tau levels
prevented behavioral deficits in transgenic mice expressing
human amyloid precursor protein and also protected both
transgenic and nontransgenic mice against excitotoxicity
, overexpression of mutant Tau in APP or APP/PS
transgenic mice does not result in dramatic effects on
neurodegeneration. One possibility might be that murine
neurons could be devoid of the downstream pathways
necessary for Aβ-induced toxicity leading to tau aggregation
in NFTs in human AD brain.
Financial support of the Alzheimer Forschung Initiative e.V.
(AFI) is gratefully acknowledged.
 J. Hardy and D. Allsop, “Amyloid deposition as the central
event in the aetiology of Alzheimer’s disease,” Trends in
Pharmacological Sciences, vol. 12, no. 10, pp. 383–388, 1991.
 H. Braak and E. Braak, “Neuropathological stageing of
Alzheimer-related changes,” Acta Neuropathologica, vol. 82,
no. 4, pp. 239–259, 1991.
 G. K. Gouras, J. Tsai, J. Naslund et al., “Intraneuronal Aβ42
vol. 156, no. 1, pp. 15–20, 2000.
 O. Wirths, G. Multhaup, and T. A. Bayer, “A modified β-
amyloid hypothesis: intraneuronal accumulation of the β-
amyloid peptide–the first step of a fatal cascade,” Journal of
Neurochemistry, vol. 91, no. 3, pp. 513–520, 2004.
 C. Duyckaerts, M.-C. Potier, and B. Delatour, “Alzheimer
disease models and human neuropathology: similarities and
differences,” Acta Neuropathologica, vol. 115, no. 1, pp. 5–38,
“Mice as models: transgenic approaches and Alzheimer’s
disease,” Journal of Alzheimer’s Disease, vol. 9, supplement 3,
pp. 133–149, 2006.
 D. Games, D. Adams, R. Alessandrini et al., “Alzheimer-type
neuropathology in transgenic mice overexpressing V717F β-
amyloid precursor protein,” Nature, vol. 373, no. 6514, pp.
deficits, Aβ elevation, and amyloid plaques in transgenic
mice,” Science, vol. 274, no. 5284, pp. 99–102, 1996.
 D. Moechars, I. Dewachter, K. Lorent et al., “Early phenotypic
changes in transgenic mice that overexpress different mutants
of amyloid precursor protein in brain,” The Journal of
Biological Chemistry, vol. 274, no. 10, pp. 6483–6492, 1999.
International Journal of Alzheimer’s Disease5
 M. A. Chishti, D.-S. Yang, C. Janus et al., “Early-onset amyloid
depositionandcognitive deficits intransgenicmice expressing
a double mutant form of amyloid precursor protein 695,” The
Journal of Biological Chemistry, vol. 276, no. 24, pp. 21562–
 C. Sturchler-Pierrat, D. Abramowski, M. Duke et al., “Two
amyloid precursor protein transgenic mouse models with
Alzheimer disease-like pathology,” Proceedings of the National
Academy of Sciences of the United States of America, vol. 94, no.
24, pp. 13287–13292, 1997.
 A. Lord, H. Kalimo, C. Eckman, X.-Q. Zhang, L. Lannfelt, and
L. N. G. Nilsson, “The Arctic Alzheimer mutation facilitates
early intraneuronal Aβ aggregation and senile plaque forma-
tion in transgenic mice,” Neurobiology of Aging, vol. 27, no. 1,
pp. 67–77, 2006.
 B. Van Broeck, G. Vanhoutte, D. Pirici et al., “Intraneuronal
amyloid β and reduced brain volume in a novel APP T714I
mouse model for Alzheimer’s disease,” Neurobiology of Aging,
vol. 29, no. 2, pp. 241–252, 2008.
 T. Tomiyama, S. Matsuyama, H. Iso, et al., “A mouse model of
amyloid β oligomers: their contribution to synaptic alteration,
abnormal Tau phosphorylation, glial activation, and neuronal
loss in vivo,” Journal of Neuroscience, vol. 30, no. 14, pp. 4845–
 D. R. Borchelt, T. Ratovitski, J. van Lare et al., “Accelerated
amyloid deposition in the brains of transgenic mice coex-
pressing mutant presenilin 1 and amyloid precursor proteins,”
Neuron, vol. 19, no. 4, pp. 939–945, 1997.
 V. Blanchard, S. Moussaoui,C.Czech et al., “Time sequence of
maturation of dystrophic neurites associated with Aβ deposits
in APP/PS1 transgenic mice,” Experimental Neurology, vol.
184, no. 1, pp. 247–263, 2003.
 J. G. Richards, G. A. Higgins, A.-M. Ouagazzal et al., “PS2APP
transgenic mice, coexpressing hPS2mut and hAPPswe, show
age-related cognitive deficits associated with discrete brain
amyloid deposition and inflammation,” Journal of Neuro-
science, vol. 23, no. 26, pp. 8989–9003, 2003.
 C. Casas, N. Sergeant, J.-M. Itier et al., “Massive CA1/2
neuronal loss with intraneuronal and N-terminal truncated
Aβ42 accumulation in a novel Alzheimer transgenic model,”
American Journal of Pathology, vol. 165, no. 4, pp. 1289–1300,
 E. M. Rib´ e, M. P´ erez, B. Puig et al., “Accelerated amyloid
deposition, neurofibrillary degeneration and neuronal loss
in double mutant APP/tau transgenic mice,” Neurobiology of
Disease, vol. 20, no. 3, pp. 814–822, 2005.
 S. Oddo, A. Caccamo, J. D. Shepherd et al., “Triple-transgenic
model of Alzheimer’s disease with plaques and tangles:
intracellular Aβ and synaptic dysfunction,” Neuron, vol. 39,
no. 3, pp. 409–421, 2003.
of Tau at S422 is enhanced by Aβ in TauPS2APP triple
transgenic mice,” Neurobiology of Disease, vol. 37, no. 2, pp.
 M. C. Irizarry, M. McNamara, K. Fedorchak, K. Hsiao, and
B. T. Hyman, “APPSw transgenic mice develop age-related Aβ
deposits and neuropil abnormalities, but no neuronal loss in
CA1,” Journal of Neuropathology and Experimental Neurology,
vol. 56, no. 9, pp. 965–973, 1997.
 M. C. Irizarry, F. Soriano, M. McNamara et al., “Aβ deposition
is associated with neuropil changes, but not with overt
neuronal loss in the human amyloid precursor protein V717F
(PDAPP) transgenic mouse,” Journal of Neuroscience, vol. 17,
no. 18, pp. 7053–7059, 1997.
 F. M. LaFerla, B. T. Tinkle, C. J. Bieberich, C. C. Haudenschild,
and G. Jay, “The Alzheimer’s Aβ peptide induces neurodegen-
eration and apoptotic cell death in transgenic mice,” Nature
Genetics, vol. 9, no. 1, pp. 21–30, 1995.
 M. E. Calhoun, K.-H. Wiederhold, D. Abramowski et al.,
“Neuron loss in APP transgenic mice,” Nature, vol. 395, no.
6704, pp. 755–756, 1998.
 B. Urbanc, L. Cruz, R. Le et al., “Neurotoxic effects of
thioflavin S-positive amyloid deposits in transgenic mice and
Alzheimer’s disease,” Proceedings of the National Academy of
Sciences of the United States of America, vol. 99, no. 22, pp.
 S. Boncristiano, M. E. Calhoun, V. Howard et al., “Neocortical
deposition in APP23 transgenic mice,” Neurobiology of Aging,
vol. 26, no. 5, pp. 607–613, 2005.
 H. Oakley, S. L. Cole, S. Logan et al., “Intraneuronal β-
amyloid aggregates, neurodegeneration, and neuron loss in
transgenic mice with five familial Alzheimer’s disease muta-
tions: potential factors in amyloid plaque formation,” Journal
of Neuroscience, vol. 26, no. 40, pp. 10129–10140, 2006.
 C. Schmitz, B. P. F. Rutten, A. Pielen et al., “Hippocampal
neuron loss exceeds amyloid Plaque load in a transgenic
mouse model of Alzheimer’s disease,” American Journal of
Pathology, vol. 164, no. 4, pp. 1495–1502, 2004.
 B. P. F. Rutten, N. M. Van der Kolk, S. Schafer et al., “Age-
related loss of synaptophysin immunoreactive presynaptic
boutons within the hippocampus of APP751SL, PS1M146L,
and APP751 SL/PS1M146L transgenic mice,” American Jour-
nal of Pathology, vol. 167, no. 1, pp. 161–173, 2005.
 H. Breyhan, O. Wirths, K. Duan, A. Marcello, J. Rettig, and
T. A. Bayer, “APP/PS1KI bigenic mice develop early synaptic
deficits and hippocampus atrophy,” Acta Neuropathologica,
vol. 117, no. 6, pp. 677–685, 2009.
 D. Z. Christensen, S. L. Kraus, A. Flohr, M.-C. Cotel,
O. Wirths, and T. A. Bayer, “Transient intraneuronal Aβ
rather than extracellular plaque pathology correlates with
neuron loss in the frontal cortex of APP/PS1KI mice,” Acta
Neuropathologica, vol. 116, no. 6, pp. 647–655, 2008.
 D. Z. Christensen, T. A. Bayer, and O. Wirths, “Intracellular
Aβ triggers neuron loss in the cholinergic system of the
APP/PS1KI mouse model of Alzheimer’s disease,” Neurobiol-
ogy of Aging, vol. 31, no. 7, pp. 1153–1163, 2008.
 H. Takahashi, I. Brasnjevic, B. P. F. Rutten, et al., “Hippocam-
pal interneuron loss in an APP/PS1 double mutant mouse and
in Alzheimer’s disease,” Brain Structure and Function, vol. 214,
no. 2-3, pp. 145–160, 2010.
 M. C. Cotel, S. Jawhar, D. Z. Christensen, et al., “Environmen-
tal enrichment fails to rescue working memory deficits, neu-
ron loss, and neurogenesis in APP/PS1KI mice,” Neurobiology
of Aging. In press.
 A. Faure, L. Verret, B. Bozon, et al., “Impaired neurogenesis,
neuronal loss, and brain functional deficits in the APPxPS1-Ki
mouse model of Alzheimer’s disease,” Neurobiology of Aging.
 S. Jawhar, A. Trawicka, C. Jenneckens, et al., “Motor deficits,
neuron loss and reduced anxiety coinciding with axonal
degeneration and intraneuronal Aβ aggregation in the 5XFAD
mouse model of Alzheimer’s disease,” Neurobiology of Aging.
 T. C. Saido, T. Iwatsubo, D. M. A. Mann, H. Shimada, Y. Ihara,
and S. Kawashima, “Dominant and differential deposition
of distinct β-amyloid peptide species, AβN3(pE), in senile
plaques,” Neuron, vol. 14, no. 2, pp. 457–466, 1995.
6 International Journal of Alzheimer’s Disease Download full-text
 S. Schilling, T. Lauber, M. Schaupp et al., “On the seeding
and oligomerization of pGlu-amyloid peptides (in vitro),”
Biochemistry, vol. 45, no. 41, pp. 12393–12399, 2006.
 Y.-M. Kuo, S. Webster, M. R. Emmerling, N. De Lima, and A.
translational modifications inhibit proteolytic degradation of
Aβ peptides of Alzheimer’s disease,” Biochimica et Biophysica
Acta, vol. 1406, no. 3, pp. 291–298, 1998.
 C. Russo, E. Violani, S. Salis et al., “Pyroglutamate-modified
amyloid β-peptides—AβN3(pE)—strongly affect cultured
neuron and astrocyte survival,” Journal of Neurochemistry, vol.
82, no. 6, pp. 1480–1489, 2002.
 O. Wirths, H. Breyhan, H. Cynis, S. Schilling, H.-U. Demuth,
and T. A. Bayer, “Intraneuronal pyroglutamate-Aβ 3-42
triggers neurodegeneration and lethal neurological deficits in
a transgenic mouse model,” Acta Neuropathologica, vol. 118,
no. 4, pp. 487–496, 2009.
 T. Tomiyama, T. Nagata, H. Shimada et al., “A new amyloid β
variant favoring oligomerization in Alzheimer’s-type demen-
tia,” Annals of Neurology, vol. 63, no. 3, pp. 377–387, 2008.
 L. M. Billings, S. Oddo, K. N. Green, J. L. McGaugh, and
F. M. LaFerla, “Intraneuronal Aβ causes the onset of early
Alzheimer’s disease-related cognitive deficits in transgenic
mice,” Neuron, vol. 45, no. 5, pp. 675–688, 2005.
 C. Bertoni-Freddari, S. L. Sensi, B. Giorgetti et al., “Decreased
presence of perforated synapses in a triple-transgenic mouse
model of Alzheimer’s disease,” Rejuvenation Research, vol. 11,
no. 2, pp. 309–313, 2008.
of Tau at S422 is enhanced by Aβ in TauPS2APP triple
transgenic mice,” Neurobiology of Disease, vol. 37, no. 2, pp.
 E. D. Roberson, K. Scearce-Levie, J. J. Palop et al., “Reducing
endogenous Tau ameliorates amyloid β-induced deficits in an
Alzheimer’s disease mouse model,” Science, vol. 316, no. 5825,
pp. 750–754, 2007.