Deciphering the mechanism underlying late-onset Alzheimer disease

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Nature Reviews Neurology (Impact Factor: 15.36). 11/2012; 9(1). DOI: 10.1038/nrneurol.2012.236
Source: PubMed
ABSTRACT
Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.

Full-text

Available from: Irene Knuesel
NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
25
Institute of
Pharmacology and
Toxicology, University
of Zurich,
Winterthurerstrasse
190, CH‑8057, Zurich,
Switzerland (D. Krstic,
I.Knuesel).
Correspondence to:
I. Knuesel
knuesel@
pharma.uzh.ch
Deciphering the mechanism underlying
late-onset Alzheimer disease
Dimitrije Krstic and Irene Knuesel
Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying
Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these
failures is the assumption that the molecular mechanism mediating the genetically determined form of the
disease is identical to the one resulting in late‑onset AD. Here, we integrate experimental evidence outside
the ‘spotlight’ of the genetic drivers of amyloid‑β (Aβ) generation published during the past two decades,
and present a mechanistic explanation for the pathophysiological changes that characterize late‑onset AD.
We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or
damaged neuronal proteins that accumulate with age, and concomitantly lead to tau‑associated impairments
of axonal integrity and transport. Such changes have several neuropathological consequences: focal
accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage,
followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites,
and generation of aggregation‑prone peptides; further tau hyperphosphorylation, ultimately resulting in
neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between
Aβ and tau‑related neuropathology, and underscores the concept that degenerating neurites represent a cause
rather than a consequence of Aβ accumulation in late‑onset AD.
Krstic, D. & Knuesel, I. Nat. Rev. Neurol. 9, 25–34 (2013); published online 27 November 2012; doi:10.1038/nrneurol.2012.236
Introduction
Alzheimer disease (AD) is the most common type of
age-related dementia, affecting approximately 24million
people worldwide, with the number of patients doub ling
every 20years as a consequence of the ageing popula tion.
1
This pandemic scenario will have not only a pro found
health and emotional influence on affected indivi-
duals and their families, but will also place a substantial
econom ic burden on society.
The disease is characterized by progressive loss of cog-
nitive abilities, severe neurodegeneration, and promi-
nent neuroinflammation.
2
Neuropathological hall marks
include proteinous aggregates in the form of senile
plaques, which are enriched in amyloid-β (Aβ) pep tides,
and neurofibrillary tangles (NFTs), consisting of hyper-
phosphorylated tau.
3
Dominant genetic effects of muta-
tions in amyloid precursor protein (APP), presenilin-1
(PS1) or PS2 are responsible for the early-onset or fa milial
form of AD. These mutations have been shown to pro-
foundly alter APP metabolism, favouring the produc-
tion of aggregation-prone Aβ species, and such findings
formed the basis of the ‘amyloid cascade hypothesis’ of
AD pathogenesis.
4
This broadly accepted hypo thesis
states that the generation of neurotoxic Aβ peptides
by β-secretase and γ-secretase constitute the cause of
AD pathophysiology, with all other disease hallmarks
develop ing as a consequence of this event.
Although the amyloid cascade hypothesis is likely to
hold true for the familial form of the disease, increas-
ing evidence suggests that the mechanisms underlying
late-onset AD—the sporadic disease form that accounts
for the vast majority of AD cases—could be different.
5
For example, in addition to the ε4 allele of the apolipo-
protein E gene (APOE)
6
—a well-known risk factor for
AD—recent genome-wide association studies identi-
fied significant correlations between polymorphisms
in genes of the innate immune system and incidence of
late-onset AD.
7,8
By contrast, no such correlation was
found between polymorphisms in genes encoding APP
or γ-secretase and incidence of late-onset AD.
9
Together
with the observation that inflammatory mediators are
abundantly present in affected brain areas
10,11
and plasma
of patients with AD,
12
these newly identified risk factors
imply that alterations in innate immunity might have
a key role in the disease aetiology, rather than being a
passive reaction to Aβ-related neuropathology.
In this article, we integrate experimental data focused
on neuroinflammation with several other neuropatho-
logical aspects of the disease that have so far been con-
sidered to be secondary to Aβ-mediated neurotoxicity,
and propose a sequence of neuropathological events
that could lead to development of late-onset AD. This
model unites many of the previously proposed mecha-
nisms underlying AD into a comprehensive view of
how the neuropathology could evolve over decades. We
first present the results that have provided the rationale
Competing interests
The authors declare no competing interests.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 1
26
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
for this hypothesis, which are then complemented by
broader literature and experimental evidence from
animal and human studies.
Inflammation hypothesis of AD
Rationale
A large body of evidence has implicated inflammatory
mediators and the innate immune system of the brain in
the aetiology of AD, as discussed below. The precise role
of inflammatory processes in the disease pathophysio-
logy has, however, been controversial, ranging from a
possible disease cause, to a by-product of the disease, or
even a beneficial response.
13
Our previous findings in mice showed that systemic
administration of the viral mimic polyriboinosinic–
polyribocytidilic acid (PolyI:C) during late gestation trig-
gered the expression of several inflammatory cytokines
in the foetal brain,
14
evoked a reduction in adult neuro-
genesis in the offspring that was accompanied by working
memory impairments,
14,15
and led to accelerated depo-
sition of aggregated proteins in the brains of the aged
offspring.
16
More recently, we demonstrated that upon
second immune stimulation with PolyI:C in adulthood,
prenatally challenged animals developed an AD-like
pheno type.
17
The ageing-associated progression of disease
in these mice was in striking similarity to that described
in patients with AD.
2
In addition, systemic immune chal-
lenge in adult transgenic AD mice led to a strong aggra-
vation of the AD-like pathology,
17
in agreement with the
observation that both acute and chronic inflammation
are associated with an increase in cognitive decline in
patients with AD.
18
Alterations in critical inflammatory
mediators might, therefore, represent a process associated
with the onset and progression of the disease in humans,
as already suggested by Sheng etal. in 1996.
19
The model
In wild-type mice, ageing is associated with increased
deposition of proteins in the brain parenchyma, and
this phenomenon is highly conserved among various
species.
16,20
Using 3D immunoelectron microscopy in
aged wild-type mice we found that, surprisingly, these
extracellular depositions originated from intracellular
spheroid-like varicosities
20
and were immunoreactive for
Key points
Despite tremendous investments in basic and clinical research, no cure or
preventive treatment for Alzheimer disease (AD) exists
A re‑evaluation of the current view of the mechanisms underlying late‑onset AD
pathology is a prerequisite for future translational approaches
Inflammatory processes are strongly correlated with AD onset and progression
in humans, and could have a pivotal role in disease aetiology
Chronic inflammation coupled with neuronal ageing induces cellular stress
and concomitant impairments in basic neuronal functions
Inflammation‑induced hyperphosphorylation and missorting of tau might
represent one of the earliest neuropathological changes in late‑onset AD
Molecular changes underlying late‑onset AD involve impairments in
cytoskeleton stability and axonal transport, which could trigger axonal
degeneration and formation of senileplaques and neurofibrillary tangles,
resulting in neuronal death
N-terminal and Aβ-containing APP fragments.
21
Some of
these structures had a budding-like morphology and con-
tained organelles, but many were detached from neurons
and/or were being engulfed by microglia and astrocytes
(Figure1, step1).
20,21
This phenomenon could, therefore,
conceivably reflect a conserved neuroprotective strategy
of postmitotic neurons to overcome age-related accumu-
lation of misfolded, damaged or aberrantly cleaved pro-
teins.
20
In line with this suggestion, a prenatal immune
challenge with its chronic elevation of proinflammatory
cytokines
17
accelerated the formation of these axonal bud-
dings, and induced the accumulation of mitochondria
and other organelles within these varicosities (Figure1,
step 2).
20
A strikingly similar budding phenomenon has
also been observed in aged rhesus monkeys,
22
which serve
as a primate model of late-onset AD.
23
Chronic inflammation and cellular stress to neurons
during ageing—owing to infection, disease, or age-
related changesinduce hyperphosphorylation and
mis sorting of tau,
17
which in turn is expected to destabi-
lize the microtubule–actin networks and impair axonal
trans port.
24
Such changes might cause the protein extru-
sion mechanism to decline or fail completely, thereby
inducing focal axonal swellings and concomitant accu-
mulation of mitochondria and other organelles (Figure1,
step3).
25,26
Disturbed energy metabolism in the axon
could induce further tau phosphorylation,
27
an additional
neuropathological event that probably facilitates the
formation of paired helical filaments (PHFs; precursor
elements of neurofibrillary tangles), as seen in double-
immune-challenged mice.
17
This outcome would lead to
further impairments in axonal transport, complete trans-
port blockade, and ultimately axonal leakage (Figure1,
step 4; Figure2a).
28
Loss of synaptic contacts and decline
in cognitive performance constitute additional structural
and functional consequences of axonal transport impair-
ments
(Figure1, step 4).
17,29
A chronic inflammatory state
also increases APP levels,
17
which may be followed by
accumulation of this protein in swollen axons
(Figure1,
steps 2–4; Figure2b).
28
In parallel with its effect on neurons, chronic sys-
temic inflammation induces a prominent activation, or
priming’, of microglial cells and extensive astrogliosis
(Figure1, step 3).
17
Recruitment of microglia towards
degenerative and/or leaking axons and axonal varicosi-
ties could, therefore, lead to over-activation of micro-
glia and production of local inflammatory ‘hot spots
that would also be expected to negatively affect nearby
neurons (Figure1, step 5). Support for this scenario is
provided by our findings in double-immune-challenged
mice in which individual accumulations of APP seem
to involve groups of several adjacent neurites, which are
surrounded by activated microglia.
17
Finally, these APP
accumulations might represent a seed for other aggrega-
tion-prone peptides (Figure1, step 5), as demonstrated
in immune-challenged transgenic AD mice.
17
On the basis of recent observations in the brains of
patients with AD,
28
we propose that axonal leakage and
release of intracellular contents—especially from dense
auto phagolysosomal vesicles
30,31
(Figure2c–e)—including
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 2
NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
27
accumulated APP
28
(Figure2b,f) into the extra cellular
matrix (Figure2a,b) leads to substantial local production
of aggregation-prone protein fragments. This scena rio is
in agreement with the abundant presence of APP cleav-
age enzymes, such as cathepsin-D
31
(Figure2e), and the
enrichment of various truncated Aβ fragments
32
and
diverse non-Aβ fragments of APP
33,34
in senile plaques.
In addition, electron micro scopy of human senile plaques
revealed, in accordance with this proposal, an abun-
dance of mitochondria and other organelles, as well as
degenerated neurites, in the plaque core.
33,35
Finally, the
pro inflammatory environment and concomitant loss of
axons might lead to formation of NFTs and neuronal cell
death (Figure1, step6). This suggestion is in agreement
with the observation that formation of NFT-like struc-
tures in AD transgenic mice—importantly, in the absence
of mutant human tau—was accompanied by aggravated
Aβ deposition, prominent neuroinflammation and con-
siderable shrinkage of cortical areas.
36
Loss of synaptic
contacts combined with persistent inflammation-induced
cellular stress probably contributes to initiation of the
patho physiology in interconnected brain areas and the
spread of the pathology across brain networks.
In the following sections, we summarize additional
experimental data from the existing literature that
support each of the proposed steps of the model.
Inflammation—a key player
Support for a key role for systemic inflammation in the
aetiology of AD was first provided by a meta-analysis of
17 epidemiological studies, which indicated that non-
steroidal anti-inflammatory drugs might decrease the
a
Healthy ageing
Step 1
Healthy aged neuron
Axonal varicosities
Bud-off granules
Microglia
Microglial priming
Aged neuron
and chronic or repeated
inammatory stress
pTau
Step 3
APP APP APP
Axonal transport impairments
Axonal varicosities
Axonal swellings and accumulation of APP
APP
APP
APP
Tau
pTau
Step 4
PHF
Tau
hyperphosphorylation
Synaptic loss
APP APP APP
APP
APP
pTau
Axonal leakage
Step 5
Aberrant processing
of APP
Diffuse plaque
formation
Impaired clearance of
dystrophic neurites and debris
PHF
APP
APP
Pathological ageing
b
Step 2
Axonal varicosities
APP synthesis
Tau phosphorylation
APP
APP
Tau
APP
pTau
Healthy aged neuron
and inammatory stress
Step 6
APP
APP
Neurobrillary
tangles
Senile
plaques
Neuroinammation
Proinammatory
cytokines
Caspase
activation
Astrogliosis
Hyperreactive microglia
Inammatory
stress
Organelle
Cellular
proteins
Aβ
Figure 1 | The inflammation hypothesis of late‑onset
Alzheimer disease. a | During healthy ageing, a conserved
protein extrusion mechanism compensates for ageing‑
dependent failures in protein clearance and degradation
(step 1). Cellular stress to ageing neurons accelerates
formation of varicosities and their extrusion into the
extracellular matrix, where they are phagocytosed by
surrounding glia (step 2). If aged neurons experience
chronic inflammation, tau becomes hyperphosphorylated
and is missorted to somatodendritic compartments, which
impairs axonal transport (steps 2 and 3).
b | Consequently, stress‑induced APP accumulates in
axonal compartments and in larger swellings (step 3).
Chronic inflammation also ‘primes’ microglia to
subsequent immune challenges (step 3). Blockade of
axonal transport leads to synaptic destabilization or loss,
and is accompanied by formation of PHFs in neurites and
membrane leakage at axonal swellings (step 4). Axonal
leakage exposes cellular proteins to lysosomal
proteinases, promoting formation of neurotoxic peptides.
Hyperreactive microglia cannot properly remove dystrophic
neurites, and create a toxic proinflammatory environment
that affects surrounding neurons. Senile amyloid‑β plaques
begin to form (step 5). In response to neuritic
degeneration, caspase activation triggers formation of
neurofibrillary tangles (step 6). Imbalances in excitatory–
inhibitory neurotransmission and the neurotoxic
proinflammatory environment initiate pathology in
interconnected brain areas. Abbreviations: APP, amyloid
precursor protein; PHF, paired helical filament.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 3
28
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
risk of AD.
37
This view is supported by two key findings
from retrospective epidemiological studies: first, plasma
levels of the inflammatory proteins C-reactive protein,
α1-antichymotrypsin and IL-6 are increased long before
clinical onset of AD and dementia;
38,39
and second, epi-
sodes of infections are strongly correlated with increased
a
b
c
d
e
f
DAPI/N-APP/Aβ
Figure 2 | Axonal swellings and leakage as a trigger of senile plaque formation in patients with Alzheimer disease.
a | Experimental support that evolution of senile plaques starts with axonal swelling and varicosities (top row, arrows) and
leakage from dystrophic axons (bottom row, arrows) in the cortex. b | Immunostaining of the cortex reveals small (left panels)
and medium‑sized (right panels) plaque‑like accumulations (arrows) enriched for hyperphosphorylated tau (upper panels)
and APP and/or amyloid‑β (lower panels). c | Autophagic vacuoles (arrowheads) loaded with proteins accumulate in
dystrophic neurites. d | Immunogold staining shows enrichment of cathepsin‑D, the APP‑degrading enzyme, in autophagic
vacuoles in swollen neurites. e,f | Dense staining of cathepsin‑D within late‑stage senile plaques (e) overlaps with staining of
accumulated amyloid‑β (f). Abbreviation: APP, amyloid precursor protein. Parts a and b are reproduced, with permission, from
Springer © Xiao, A. W. etal. Neurosci. Bull. 27, 287–299 (2011). Parts c and e are reproduced, with permission, from Elsevier
Ltd © Nixon, R. A. & Yang, D. S. Neurobiol. Dis. 43, 38–45 (2011). Part d is reproduced, with permission, from Wolters Kluwer
Health © Nixon, R. A. etal. J.Neuropathol. Exp. Neurol. 64, 113–122 (2005). Part f is reproduced from Krstic, D. etal.
J.Neuroinflammation 9, 151 (2012), which is published under an open‑access license by Biomed Central.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 4
NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
29
likelihood of a diagnosis of dementia.
40
Randomized con-
trolled trials, however, failed to show a beneficial effect of
anti-inflammatory drugs in patients with symptomatic
AD or mild cognitive impairment.
41,42
Nevertheless,
extended treatment of asymptomatic individuals with the
anti-inflammatory drug naproxen reduced the incidence
of AD, supporting a beneficial effect of anti-inflammatory
drugs only when administered in early, asymptomatic
phases of the disease.
43
Interestingly, patients with high plaque burden with-
out dementia—so-called high-pathology controls
44,45
show almost no evidence of neuroinflammation
46–48
and
neuro degeneration.
46
These findings are in accordance
with results from several transgenic mouse lines that
express human versions of AD-inducing mutated genes,
which show no evidence of strong neuroinflammatory
responses nor widespread progressive neuronal cell
death.
49
Of further interest, Aβ
1-42
levels in the brains of
high- pathology controls were much higher than those in
the brains of aged-matched patients with AD,
50
in agree-
ment with a controversial proposal that Aβ
1-42
may be
protective rather than toxic,
51
as further discussed below.
In addition, PET imaging studies revealed that cogni-
tive status in patients with AD is inversely correlated
with microglial activation, but not Aβ load.
52,53
Finally,
in accordance with the above mentioned genome-wide
association studies,
7,8
chronic inflammatory diseases and
conditions in humans, including atherosclerosis, obesity,
diabetes, depression, and periodontitis,
54–60
all represent
either risk factors for or correlate strongly with the risk
of late-onset AD.
Aged and primed microglia
The increase in proinflammatory cytokines in the serum
that accompanies systemic inflammation has been shown
to play a fundamental part in communication between
the brain and immune system. Such communication
occurs through activation of central innate immunity and
initiation of a behavioural response, known as sickness
behaviour.
61
Apart from endothelial cells—which have
an important role in blood–brain communication
62
microglia seem to be crucially involved in regulation
of the brains response to systemic inflammation. For
example, systemic inflammation in mice induced by the
viral mimic PolyI:C,
63
the bacterial endotoxin lipopoly-
saccharide (LPS)
64,65
or by peripheral infusion of the
proinflammatory cytokine IL-1β
66
was shown to activate
microglia and induce the expression of brain-derived pro-
inflammatory cytokines. In agreement with these find-
ings, sepsis induces microglial activation in humans.
67
Moreover, chronic or repeated systemic inflamma tion
in mice primes microglia to induce an exaggerated
proinflammatory response to subsequent stimulations.
68
Consistent with these findings, microarray data from
aged human and murine brain tissue point to increased
transcriptional activity of genes related to cellular stress
and inflammation in the course of ageing,
10,69,70
a state
that has been termed ‘inflammaging’.
71
Hence, the obser-
vation that sickness behaviour at young age is relatively
benign, whereas systemic inflammation in the elderly
can lead to delirium,
72
could be explained by an age-
associated priming of microglia.
73,74
In rodents, acute
systemic infection in aged, but not young, animals leads
to hippocampus-dependent cognitive impairments,
75,76
and exaggerated and prolonged upregulation of the pro-
inflammatory cytokine IL-1β.
77,78
Chronic inflammatory
conditions during ageing are, therefore, expected to pro-
foundly affect the response of microglia towards damage
signals that are released by degenerating neurons.
A broadly accepted view holds that microglia are
recruited to clear Aβ aggregates,
79
but ablation of micro-
glia does not influence the formation and maintenance
of Aβ deposits in a mouse model of AD.
80
Similarly, after
uptake of soluble and fibrillary Aβ by microglia, a large
fraction of both species are released without degrada-
tion.
81,82
Microglia might instead be primarily recruited
to clear the fragmented and/or apoptotic neurons and
neurites within the senile plaques,
83
as occurs during
neurodevelopment.
84
As proposed previously,
33
micro-
glial involvement in internalization of Aβ aggregates
could, therefore, be interpreted as part of the process of
clearing degenerating neurites that contain misfolded
and damaged proteins.
Finally, besides being hyper reactive in AD,
85
microglia
may also become dysfunctional or senescent as disease
progresses, as indicated by the association of fragmented
microglia with tau pathology.
86
This observation would
also explain the attenuation of neuroinflammation in
AD patients with increasing age,
87
and supports the role
of inflammation early in the pathogenesis of AD. Hence,
in AD, a hyperreactive microglial state and increased
secretion of proinflammatory mediators, combined with
downregulated phagocytic functions, might lead to ineffi-
cient clearance of degenerated neurites. Impaired clear-
ance mechanisms may produce not only a neurotoxic
environment for surrounding neurons, but also a local
‘hot spot’ for accumulation of aggregation-prone peptides.
Early cytoskeletal impairments
Systemic administration of LPS, a potent inflamma-
tory agent, induces hyperphosphorylation of tau in
neurons
88
—a process that is mediated by activated micro-
glia.
88–90
Similarly, a recent study showed that induced
airway allergy in mice modified the brain inflammatory
status and increased phosphorylation of tau.
91
Given
that phosphorylation of tau is crucial for regulation of
microtubule stability and axonal transport,
92
and that
hyperphosphorylated tau not only affects the micro-
tubule network but also induces accumulation of fila-
mentous actin and formation of actin-rich rods,
93
these
observations could provide a link between inflamma-
tory processes and cytoskeletal abnormalities observed
in postmortem examination of all AD cases.
94
As previ-
ously proposed,
95
these cytoskeletal abnormalities would
affected axoplasmatic flow, as seen in patients with
AD,
96,97
and would impair the function of the Golgi appa-
ratus. Such an outcome could explain why this organelle
has a fragmented and atrophic morphology in neurons
of patients with AD.
98
Interestingly, over expression of
APOEε4, as well as mutations in PS1 and APP, also affect
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 5
30
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
tau phosphorylation, axonal transport, and neuronal
dystrophy
99–102
in an Aβ-independent manner, which
suggests a possible converging process underlying the
familial and sporadic forms of the disease.
Finally, on the basis of analysis of an unbiased selec-
tion of postmortem human brains in the age range
of 1–100years, Heiko Braak and colleagues recently
reported that tau-related neuronal changes appeared
considerably earlier than did amyloid deposition, and
that in more than half of investigated cases, abnormal
tau protein occurred without the presence of Aβ depos-
its.
103
These observations indicate that impairments in
neuronal integrity owing to hyperphosphorylation of
tau could constitute an early neuropathological event
that precedes deposition of the classical AD hallmarks,
potentially by decades.
Inflammation and cellular stress
Numerous inflammatory stimuli, such as IL-1β and
IFN-γ, induce an increase in protein synthesis through
the mTOR (mammalian target of rapamycin) signal-
ling pathway.
104
A large fraction of newly generated
proteins, however, are defective in folding, translation,
and/or assembly. This inflammation-induced pool of
damaged proteins are selectively degraded through the
immunoproteasome
105
—a fast-acting proteasome variant
that protects cells from the damaging effects of neuro-
inflammatory processes associated with ageing.
106
In the
brains of elderly individuals, aberrant, chronic elevation of
inflammatory cytokines, which can result from persistent
infections or inflammatory conditions, could conceiv-
ably impair or even inhibit immuno proteasome activity
in ageing neurons,
107
thereby enhancing the intracellular
accumulation of misfolded or damaged proteins.
Immune challenge either by the bacterial mimic LPS
or by direct application of IL-1β results in pronounced
increase in APP synthesis in primary cultured neurons
19,108
as well as in the brains of rats and mice.
19,109
Furthermore,
several studies have provided experimental evidence that
traumatic head injury in rodents and humans can result
in significant elevation in APP levels,
110,111
as well as Aβ
generation and amyloid plaque deposition.
112,113
In line
with the high turnover, rapid anterograde transport, and
processing of APP in distal compartments,
114–116
geneti-
cally induced fibre tract degeneration in the gracile axonal
dystrophy mouse provokes rapid axonal accumulation of
APP and Aβ.
117
Moreover, disruption of axonal and den-
dritic transport following impaired lysosomal proteo-
lysis is accompanied by increased levels of C-terminally
cleaved APP fragments,
118
which indicates that a combina-
tion of increased synthesis and impaired axonal transport
of APP induces its rapid accumulation in neurites with
subsequent aberrant cleavage. Notably, however, APP was
recently shown to be required for maintenance of distal
synaptic connections in APP/APLP2 knockout mice.
119
Hence, the increase in APP synthesis—so far exclusively
considered as a trigger of accelerated production of
neuro toxic’ Aβ peptides—may be a physiological reac-
tion of neurons to ensure stabilization of their synapses
under stress conditions.
From varicosities to degeneration
The axonal enlargements described above that involve
accumulation of multiple axonal cargoes and cyto-
skeletal proteins occur in transgenic AD mice,
120,121
aged
monkeys,
22,122
and patients with AD,
123
and precede the
typical disease-related pathology. Complementing these
findings, Xiao and colleagues recently showed that
extensively swollen axons and varicosities, accompanied
by pronounced axonal leakage, are associated with the
origin and development of neuritic plaques in patients
with AD
28
(Figure2a,b).
Swollen axons and varicosities in patients with AD
contain high levels of APP
28
and autophagic vacuoles that
are enriched in PS1,
123
cathepsin-D and cathepsin-B
124
lysosomal proteases with β-secretase activity
125
—as well
as other lysosomal proteins. It is plausible, therefore, that
the release of intracellular contents into the extracellular
matrix via axonal leakage
28
could bring APP into close
proximity with APP-specific proteases. Aberrant APP
processing at these locations is in agreement with the
findings that Aβ plaques in patients with AD contain not
only Aβ
1–40
and Aβ
1–42
, but also substantial amounts of
truncated Aβ peptides,
32
as well as large amounts of APP
and its non-amyloidogenic fragments.
33,34
Interestingly,
only truncated Aβ peptides isolated from the brains of
patients with AD formed dimers,
32
which are suggested
to be principal neurotoxic species of Aβ.
126
The pro-
posed scenario of plaque formation could also explain
the increase in aberrantly cleaved (by cathepsin-D)
fragments of Apo-E that are observed in patients with
AD.
127,128
Hence, in contrast to the familial form, in late-
onset AD, aberrant processing of accumulated APP seems
to be secon dary to inflammation-induced axonopathy
(Figure2). In addition, physiologically produced Aβ
1–42
peptide may not represent the neurotoxic Aβ species,
but an acute-phase reactant that is triggered by ongoing
neurodegenerative processes, as suggested previously.
51
Although axonal degeneration precedes and may pre-
cipitate plaque formation, pronounced cell death and
progressive neurodegeneration are late features in AD.
Therefore, certain transport processes might remain
active at early stages of the disease, despite the overt
axonopathy and amyloid plaque deposition. Indeed,
in a transgenic mouse model of AD, dystrophic axons
associated with Aβ plaques remained continuous and
connected to viable neuronal somata.
129
Nevertheless,
the lack of stabilizing presynaptic proteins, including
A P P,
119
is expected to trigger synaptic disconnection—
a well-described feature of early-stage AD patho-
physiology.
130
Secondary impairments in mitochondrial
transport and energy supply,
131
and aberrant maturation
of autophagic vacuoles,
30
are likely to further promote
axonal de generation and induce neuronal death.
Formation of neurofibrillary tangles
Dystrophic axons and dendrites associated with
Aβ plaques are ideally placed to link Aβ with the
microtubule-stabilizing protein tau and NFT neuro-
pathology. Although NFTs can exist in the absence
of Aβ accumulation,
103
a widely accepted view is that
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 6
NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
31
amyloid-related changes precede the tau-associated
neuro pathology.
4
The direct or indirect mechanistic
relation ship between these two AD hallmarks, however,
has not yet been resolved. Moreover, investigations into
the molecular link between amyloid and NFTs have
mainly, if not exclusively, centred on the involvement of
Aβ peptides on tau localization and phosphorylation.
132
The observation that neuritic plaques develop gradu-
ally in the projection areas of NFT-bearing neurons
133
indicates that NFTs develop in neurons whose neurites
are involved in the formation of senile plaques. Support
for this idea has been provided by immunolabelling and
postmortem tracing studies in brain tissue from patients
with AD, which showed that dystrophic and swollen and/
or leaking neurites participating in plaque formation
also contain hyperphosphorylated tau.
134,28
In addition,
caspase activation was shown to precede the formation
of tau aggregates, and caspase-cleaved tau was sufficient
to induce the formation of NFTs.
135
Hence, similar to
induction of caspase activation following axonal swell-
ing during traumatic axonal injury,
136
caspase activa-
tion—and, thereby, NFT formation—might be triggered
by axonal transport blockade or leakage.
137
Notably, these data support the concept that NFTs form
in response to the axonopathy with its aberrant accu-
mulation and cleavage of APP and concomitant plaque
formation, and not as a consequence of Aβ pathology.
In line with this view, in mice over-expressing mutated
human tau, NFT formation is preceded by axonopathy
in the absence of amyloid plaque formation.
138
Moreover,
genetic ablation of kinesin light chain 1, which induces an
age-dependent axonopathy, is accompanied by tau hyper-
phosphorylation, as evaluated using several AD-specific
tau antibodies.
138
Conclusion
For the past two decades, the general assumption that the
molecular mechanism underlying the genetically deter-
mined form of AD is identical to the one determining the
late-onset variant of the disease has resulted in an almost
exclusive focus of our experimental and translational
research on Aβ species and its effects on neuronal integ-
rity and functions. However, despite more than 66,000
publications, numerous clinical investigations, and inno-
vative drug developments, we remain unable to even slow
disease progression. Re-evaluation of our knowledge of
the late-onset form of AD, which accounts for the majority
of patients, is therefore of highest priority. In this article,
we have integrated numerous experimental findings with
a focus beyond Aβ to propose a sequence of pathological
events that might lead to development of late-onsetAD
in humans. We suggest naming this integrated view
of how the neuropathology evolves over decades ‘the
in flammation hypothesis of AD, as inflammation induced
by infection, disease, or age-related changes could be the
main cellular stressor after 80 or more years of life. In
addition, traumatic head injury, micro-strokes and other
vascular dysfunctions associated with increased risk of
AD probably trigger the pathological cascade described
here via secondary neuroinflammatory reactions.
In summary, in late-onset AD—in contrast to the
familial form of the disease—chronic inflammatory
conditions may represent a major trigger of pathology
by inducing phospho-tau-related cytoskeletal abnormali-
ties and concomitant impairments of axonal transport.
These changes could lead to age-dependent formation of
axonal swellings, focal accumulation of mitochondria,
and transport and degradation of organelles. Membrane
leakage at the sites of axonal swellings could serve as a
seed for the formation of senile plaques, thereby trig-
gering an innate immune response of the brain. Axonal
transport impairments would also affect the stability
of distal synapses and facilitate the formation of NFTs.
Together with persistent neuroinflammatory reactions,
these changes are expected to lead to prominent neuro-
degeneration and the spread of pathology. We argue,
therefore, that extra cellular Aβ plaques originate from
intracellular APP accumulations and are secondary to
degeneration of neurons. Consequently, therapeutic
strategies to remove plaques using specific antibodies,
or to prevent plaque formation through inhibition of
β-secretase or γ-secretase, would have little—if any—
effect on disease initiation and probably also progres-
sion. Finally, we propose that the primary pathological
event in AD is inflammation-induced and stress-induced
mislocalization and hyperphosphorylation of tau, with
subsequent impairment of axonal transport.
We are aware that the experimental results and obser-
vations reviewed here represent only a fraction of all
the published data on late-onset AD, and that further
investigations are needed to fully delineate the molecular
mechanisms that initiate and drive the pathology in late-
onset AD. Hence we truly hope that scientists and clini-
cians will add their data to confirm, refine, adjust, and
extend our proposed sequence of events. Nevertheless,
we strongly believe that the proposed model with its solid
experimental backup provides a first step for the initia-
tion and support of new research directions in the AD
field beyond Aβ.
Review criteria
Full‑text, English‑language articles were included in
the search, without restrictions on publication date.
We searched the MEDLINE and PubMed databases,
and used the Google search engine, for terms
including: “Alzheimer disease”, “inflammation”,
“neuroinflammation, “ageing”, “GWAS”, “infection”,
“cognition”, “dementia”, “tau hyperphosphorylation”,
“amyloid precursor protein”, “axonal transport”,
“cytoskeleton abnormalities”, “oxidative stress”,
“lysosomes”, “autophagy”, “protein degradation”,
“microglia”, “senile plaques”, “neurofibrillary tangle”,
“neurodegeneration”, and “caspases”. Reference lists
of selected articles were searched to identify further
references. Our search for observations in AD was based
on selected reviews on clinical and pathophysiological
aspects of AD, and on PubMed searches using
the above terms in combination with: “oldest‑old”,
“nonagenarians”, “without/no dementia”, “high
pathology”, AND the filter “species: human”.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 7
32
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
1. Ferri, C.P. etal. Global prevalence of dementia:
a Delphi consensus study. Lancet 366,
2112–2117 (2005).
2. Castellani, R.J., Rolston, R.K. & Smith, M.A.
Alzheimer disease. Dis. Mon. 56, 484–546
(2010).
3. Serrano‑Pozo, A., Frosch, M.P., Masliah, E. &
Hyman, B.T. Neuropathological alterations in
Alzheimer disease. Cold Spring Harb. Perspect.
Med. 1, a006189 (2011).
4. Hardy, J.A. & Higgins, G.A. Alzheimer’s disease:
the amyloid cascade hypothesis. Science 256,
184–185 (1992).
5. Herrup, K. Reimagining Alzheimer’s disease
—an age‑based hypothesis. J. Neurosci. 30,
16755–16762 (2010).
6. Corder, E.H. etal. Gene dose of apolipoprotein E
type 4 allele and the risk of Alzheimer’s disease
in late onset families. Science 261, 921–923
(1993).
7. Harold, D. etal. Genome‑wide association study
identifies variants at CLU and PICALM
associated with Alzheimer’s disease. Nat. Genet.
41, 1088–1093 (2009).
8. Lambert, J.C. etal. Genome‑wide association
study identifies variants at CLU and CR1
associated with Alzheimer’s disease. Nat. Genet.
41, 1094–1099 (2009).
9. Gerrish, A. etal. The role of variation at AβPP,
PSEN1, PSEN2, and MAPT in late onset
Alzheimer’s disease. J. Alzheimers Dis. 28,
377–387 (2012).
10. Cribbs, D.H. etal. Extensive innate immune
gene activation accompanies brain aging,
increasing vulnerability to cognitive decline and
neurodegeneration: a microarray study.
J.Neuroinflammation 9, 179 (2012).
11. McGeer, P.L. & McGeer, E.G. Local
neuroinflammation and the progression of
Alzheimer’s disease. J. Neurovirol. 8, 529–538
(2002).
12. Swardfager, W. etal. A meta‑analysis of
cytokines in Alzheimer’s disease. Biol. Psychiatry
68, 930–941 (2010).
13. Wyss‑Coray, T. Inflammation in Alzheimer
disease: driving force, bystander or beneficial
response? Nat. Med. 12, 1005–1015 (2006).
14. Meyer, U. etal. The time of prenatal immune
challenge determines the specificity of
inflammation‑mediated brain and behavioral
pathology. J. Neurosci. 26, 4752–4762 (2006).
15. Meyer, U. etal. Relative prenatal and postnatal
maternal contributions to schizophrenia‑related
neurochemical dysfunction after inutero
immune challenge. Neuropsychopharmacology
33, 441–456 (2008).
16. Knuesel, I. etal. Age‑related accumulation of
Reelin in amyloid‑like deposits. Neurobiol. Aging
30, 697–716 (2009).
17. Krstic, D. etal. Systemic immune challenges
trigger and drive Alzheimer‑like neuropathology
in mice. J. Neuroinflammation 9, 151 (2012).
18. Holmes, C. etal. Systemic inflammation and
disease progression in Alzheimer disease.
Neurology 73, 768–774 (2009).
19. Sheng, J.G. etal. Invivo and invitro evidence
supporting a role for the inflammatory cytokine
interleukin‑1 as a driving force in Alzheimer
pathogenesis. Neurobiol. Aging 17, 761–766
(1996).
20. Doehner, J., Genoud, C., Imhof, C., Krstic, D. &
Knuesel, I. Extrusion of misfolded and
aggregated proteins—a protective strategy of
aging neurons? Eur. J. Neurosci. 35, 1938–1950
(2012).
21. Doehner, J., Madhusudan, A., Konietzko, U.,
Fritschy, J.M. & Knuesel, I. Co‑localization of
Reelin and proteolytic AβPP fragments in
hippocampal plaques in aged wild‑type mice.
J.Alzheimers Dis. 19, 1339–1357 (2010).
22. Fiala, J.C., Feinberg, M., Peters, A. & Barbas, H.
Mitochondrial degeneration in dystrophic
neurites of senile plaques may lead to
extracellular deposition of fine filaments. Brain
Struct. Funct. 212, 195–207 (2007).
23. Price, D.L. etal. Aged non‑human primates:
an animal model of age‑associated
neurodegenerative disease. Brain Pathol. 1,
287–296 (1991).
24. Kanaan, N.M. etal. Pathogenic forms of tau
inhibit kinesin‑dependent axonal transport
through a mechanism involving activation of
axonal phosphotransferases. J. Neurosci. 31,
9858–9868 (2011).
25. Shahpasand, K. etal. Regulation of
mitochondrial transport and inter‑microtubule
spacing by tau phosphorylation at the sites
hyperphosphorylated in Alzheimer’s disease.
J.Neurosci. 32, 2430–2441 (2012).
26. Shemesh, O.A., Erez, H., Ginzburg, I. &
Spira,M.E. Tau‑induced traffic jams reflect
organelles accumulation at points of microtubule
polar mismatching. Traffic 9, 458–471 (2008).
27. Iijima‑Ando, K. etal. Loss of axonal mitochondria
promotes tau‑mediated neurodegeneration and
Alzheimer’s disease‑related tau phosphorylation
via PAR‑1. PLoS Genet. 8, e1002918 (2012).
28. Xiao, A.W. etal. The origin and development of
plaques and phosphorylated tau are associated
with axonopathy in Alzheimer’s disease.
Neurosci. Bull. 27, 287–299 (2011).
29. Hoover, B.R. etal. Tau mislocalization to
dendritic spines mediates synaptic dysfunction
independently of neurodegeneration. Neuron 68,
1067–1081 (2010).
30. Nixon, R.A. etal. Extensive involvement of
autophagy in Alzheimer disease: an immuno‑
electron microscopy study. J. Neuropathol. Exp.
Neurol. 64, 113–122 (2005).
31. Nixon, R.A. & Yang, D.S. Autophagy failure in
Alzheimer’s disease—locating the primary
defect. Neurobiol. Dis. 43, 38–45 (2011).
32. Sergeant, N. etal. Truncated beta‑amyloid
peptide species in pre‑clinical Alzheimer’s
disease as new targets for the vaccination
approach. J. Neurochem. 85, 1581–1591
(2003).
33. McGeer, P.L. etal. Immunohistochemical
localization of beta‑amyloid precursor protein
sequences in Alzheimer and normal brain tissue
by light and electron microscopy. J. Neurosci.
Res. 31, 428–442 (1992).
34. Perry, G. etal. Immunolocalization of the amyloid
precursor protein within the senile plaque. Prog.
Clin. Biol. Res. 317, 1021–1025 (1989).
35. Malamud, N. & Hirano, A. Atlas of
Neuropathology 2
nd
edn 314–327 (University of
California Press, Berkley, Los Angeles, London,
1974).
36. Kocherhans, S. etal. Reduced Reelin
expression accelerates amyloid‑beta plaque
formation and tau pathology in transgenic
Alzheimer’s disease mice. J. Neurosci. 30,
9228–9240 (2010).
37. McGeer, P.L., Schulzer, M. & McGeer, E.G.
Arthritis and anti‑inflammatory agents as
possible protective factors for Alzheimer’s
disease: a review of 17 epidemiologic studies.
Neurology 47, 425–432 (1996).
38. Schmidt, R. etal. Early inflammation and
dementia: a 25‑year follow‑up of the Honolulu–
Asia Aging Study. Ann. Neurol. 52, 168–174
(2002).
39. Engelhart, M.J. etal. Inflammatory proteins in
plasma and the risk of dementia: the Rotterdam
Study. Arch. Neurol. 61, 668–672 (2004).
40. Dunn, N., Mullee, M., Perry, V.H. & Holmes, C.
Association between dementia and infectious
disease: evidence from a case–control study.
Alzheimer Dis. Assoc. Disord. 19, 91–94 (2005).
41. Aisen, P.S. etal. Effects of rofecoxib or naproxen
vs placebo on Alzheimer disease progression:
a randomized controlled trial. JAMA 289,
2819–2826 (2003).
42. Thal, L.J. etal. A randomized, double‑blind, study
of rofecoxib in patients with mild cognitive
impairment. Neuropsychopharmacology 30,
1204–1215 (2005).
43. Breitner, J.C. etal. Extended results of the
Alzheimer’s disease anti‑inflammatory
prevention trial. Alzheimers Dement. 7, 402–411
(2011).
44. Crystal, H. etal. Clinico‑pathologic studies in
dementia: nondemented subjects with
pathologically confirmed Alzheimer’s disease.
Neurology 38, 1682–1687 (1988).
45. Snowdon, D.A. Aging and Alzheimer’s disease:
lessons from the Nun Study. Gerontologist 37,
150–156 (1997).
46. Lue, L.F., Brachova, L., Civin, W.H. & Rogers, J.
Inflammation, Aβ deposition, and neurofibrillary
tangle formation as correlates of Alzheimer’s
disease neurodegeneration. J. Neuropathol. Exp.
Neurol. 55, 1083–1088 (1996).
47. Morimoto, K. etal. Expression profiles of
cytokines in the brains of Alzheimer’s disease
(AD) patients compared to the brains of non‑
demented patients with and without increasing
AD pathology. J. Alzheimers Dis. 25, 59–76
(2011).
48. Parachikova, A. etal. Inflammatory changes
parallel the early stages of Alzheimer disease.
Neurobiol. Aging 28, 1821–1833 (2007).
49. Schwab, C., Hosokawa, M. & McGeer, P.L.
Transgenic mice overexpressing amyloid beta
protein are an incomplete model of Alzheimer
disease. Exp. Neurol. 188, 52–64 (2004).
50. Maarouf, C.L. etal. Alzheimer’s disease and
non‑demented high pathology control
nonagenarians: comparing and contrasting the
biochemistry of cognitively successful aging.
PLoS ONE 6, e27291 (2011).
51. Castellani, R.J. etal. Reexamining Alzheimer’s
disease: evidence for a protective role for
amyloid‑β protein precursor and amyloid‑β.
J.Alzheimers Dis. 18, 447–452 (2009).
52. Edison, P. etal. Microglia, amyloid, and cognition
in Alzheimer’s disease: an [
11
C](R)PK11195‑PET
and [
11
C]PIB‑PET study. Neurobiol. Dis. 32,
412–419 (2008).
53. Yokokura, M. etal. Invivo changes in microglial
activation and amyloid deposits in brain regions
with hypometabolism in Alzheimer’s disease.
Eur. J. Nucl. Med. Mol. Imaging 38, 343–351
(2011).
54. Andersen, K., Lolk, A., Kragh‑Sorensen, P.,
Petersen, N.E. & Green, A. Depression and the
risk of Alzheimer disease. Epidemiology 16,
233–238 (2005).
55. Balakrishnan, K. etal. Plasma Aβ42 correlates
positively with increased body fat in healthy
individuals. J. Alzheimers Dis. 8, 269–282 (2005).
56. Biessels, G.J. & Kappelle, L.J. Increased risk of
Alzheimer’s disease in TypeII diabetes: insulin
resistance of the brain or insulin‑induced
amyloid pathology? Biochem. Soc. Trans. 33,
1041–1044 (2005).
57. Casserly, I. & Topol, E. Convergence of
atherosclerosis and Alzheimer’s disease:
inflammation, cholesterol, and misfolded
proteins. Lancet 363, 1139–1146 (2004).
58. Dowlati, Y. etal. A meta‑analysis of cytokines in
major depression. Biol. Psychiatry 67, 446–457
(2010).
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 8
NATURE REVIEWS
|
NEUROLOGY VOLUME 9
|
JANUARY 2013
|
33
59. Kamer, A.R. etal. TNF‑α and antibodies to
periodontal bacteria discriminate between
Alzheimer’s disease patients and normal
subjects. J. Neuroimmunol. 216, 92–97 (2009).
60. Ownby, R.L., Crocco, E., Acevedo, A., John, V. &
Loewenstein, D. Depression and risk for
Alzheimer disease: systematic review, meta‑
analysis, and metaregression analysis. Arch.
Gen. Psychiatry 63, 530–538 (2006).
61. Tizard, I. Sickness behavior, its mechanisms and
significance. Anim. Health Res. Rev. 9, 87–99
(2008).
62. Zlokovic, B.V. Neurovascular pathways to
neurodegeneration in Alzheimer’s disease and
other disorders. Nat. Rev. Neurosci. 12,
723–738 (2011).
63. Cunningham, C., Campion, S., Teeling, J.,
Felton,L. & Perry, V.H. The sickness behaviour
and CNS inflammatory mediator profile induced
by systemic challenge of mice with synthetic
double‑stranded RNA (poly I:C). Brain Behav.
Immun. 21, 490–502 (2007).
64. Hannestad, J. etal. Endotoxin‑induced systemic
inflammation activates microglia: [
11
C]PBR28
positron emission tomography in nonhuman
primates. Neuroimage 63, 232–239 (2012).
65. Pitossi, F., del Rey, A., Kabiersch, A. &
Besedovsky, H. Induction of cytokine transcripts
in the central nervous system and pituitary
following peripheral administration of endotoxin
to mice. J. Neurosci. Res. 48, 287–298 (1997).
66. Anisman, H., Gibb, J. & Hayley, S. Influence of
continuous infusion of interleukin‑1β on
depression‑related processes in mice:
corticosterone, circulating cytokines, brain
monoamines, and cytokine mRNA expression.
Psychopharmacology (Berl.) 199, 231–244
(2008).
67. Lemstra, A.W. etal. Microglia activation in sepsis:
a case–control study. J.Neuroinflammation 4, 4
(2007).
68. Puentener, U., Booth, S.G., Perry, V.H. &
Teeling,J.L. Long‑term impact of systemic
bacterial infection on the cerebral vasculature and
microglia. J. Neuroinflammation 9, 146 (2012).
69. Lee, C.K., Weindruch, R. & Prolla, T.A. Gene‑
expression profile of the ageing brain in mice.
Nat. Genet. 25, 294–297 (2000).
70. Lu, T. etal. Gene regulation and DNA damage in
the ageing human brain. Nature 429, 883–891
(2004).
71. Franceschi, C. etal. Inflammaging and anti‑
inflammaging: a systemic perspective on aging
and longevity emerged from studies in humans.
Mech. Ageing Dev. 128, 92–105 (2007).
72. Cunningham, C. & Maclullich, A.M. At the
extreme end of the psychoneuroimmunological
spectrum: delirium as a maladaptive sickness
behaviour response. Brain. Behav. Immun.
http://dx.doi.org/10.1016/j.bbi.2012.07.012.
73. Norden, D.M. & Godbout, J.P. Microglia of the
aged brain: primed to be activated and resistant
to regulation. Neuropathol. Appl. Neurobiol.
http://dx.doi.org/10.1111/j.1365‑2990.
2012.01306.x.
74. Wynne, A.M., Henry, C.J. & Godbout, J.P.
Immune and behavioral consequences of
microglial reactivity in the aged brain. Integr.
Comp. Biol. 49, 254–266 (2009).
75. Barrientos, R.M. etal. Peripheral infection and
aging interact to impair hippocampal memory
consolidation. Neurobiol. Aging 27, 723–732
(2006).
76. Godbout, J.P. etal. Exaggerated
neuroinflammation and sickness behavior in
aged mice following activation of the peripheral
innate immune system. FASEB J. 19, 1329–1331
(2005).
77. Barrientos, R.M. etal. Time course of
hippocampal IL‑1 β and memory consolidation
impairments in aging rats following peripheral
infection. Brain. Behav. Immun. 23, 46–54
(2009).
78. Henry, C.J., Huang, Y., Wynne, A.M. &
Godbout,J.P. Peripheral lipopolysaccharide
(LPS) challenge promotes microglial
hyperactivity in aged mice that is associated
with exaggerated induction of both pro‑
inflammatory IL‑1β and anti‑inflammatory IL‑10
cytokines. Brain Behav. Immun. 23, 309–317
(2009).
79. Lee, C.Y. & Landreth, G.E. The role of microglia
in amyloid clearance from the AD brain. J. Neural
Transm. 117, 949–960 (2010).
80. Grathwohl, S.A. etal. Formation and
maintenance of Alzheimer’s disease β‑amyloid
plaques in the absence of microglia. Nat.
Neurosci. 12, 1361–1363 (2009).
81. Chung, H., Brazil, M.I., Soe, T.T. & Maxfield, F.R.
Uptake, degradation, and release of fibrillar and
soluble forms of Alzheimer’s amyloid β‑peptide
by microglial cells. J. Biol. Chem. 274,
32301–32308 (1999).
82. Njie, E.G. etal. Exvivo cultures of microglia from
young and aged rodent brain reveal age‑related
changes in microglial function. Neurobiol. Aging
33, 195.e1–195.e12 (2012).
83. Sheng, J.G., Mrak, R.E. & Griffin, W.S. Neuritic
plaque evolution in Alzheimer’s disease is
accompanied by transition of activated microglia
from primed to enlarged to phagocytic forms.
Acta Neuropathol. 94, 1–5 (1997).
84. Peri, F. & Nusslein‑Volhard, C. Live imaging of
neuronal degradation by microglia reveals a role
for v0‑ATPase a1 in phagosomal fusion invivo.
Cell 133, 916–927 (2008).
85. McGeer, P.L., Itagaki, S., Tago, H. &
McGeer,E.G. Occurrence of HLA‑DR reactive
microglia in Alzheimer’s disease. Ann. NY Acad.
Sci. 540, 319–323 (1988).
86. Streit, W.J., Braak, H., Xue, Q.S. & Bechmann, I.
Dystrophic (senescent) rather than activated
microglial cells are associated with tau
pathology and likely precede neurodegeneration
in Alzheimer’s disease. Acta Neuropathol. 118,
475–485 (2009).
87. Hoozemans, J.J., Rozemuller, A.J., van
Haastert, E.S., Eikelenboom, P. & van
Gool,W.A. Neuroinflammation in Alzheimer’s
disease wanes with age. J. Neuroinflammation 8,
171 (2011).
88. Bhaskar, K. etal. Regulation of tau pathology by
the microglial fractalkine receptor. Neuron 68,
19–31 (2010).
89. Gorlovoy, P., Larionov, S., Pham, T.T. &
Neumann,H. Accumulation of tau induced in
neurites by microglial proinflammatory
mediators. FASEB J. 23, 2502–2513 (2009).
90. Li, Y., Liu, L., Barger, S.W. & Griffin, W.S.
Interleukin‑1 mediates pathological effects of
microglia on tau phosphorylation and on
synaptophysin synthesis in cortical neurons
through a p38‑MAPK pathway. J. Neurosci. 23,
1605–1611 (2003).
91. Sarlus, H. etal. Allergy influences the
inflammatory status of the brain and enhances
tau phosphorylation. J. Cell. Mol. Med. 16,
2401–2412 (2012).
92. Johnson, G.V. & Stoothoff, W.H. Tau
phosphorylation in neuronal cell function and
dysfunction. J. Cell Sci. 117, 5721–5729
(2004).
93. Fulga, T.A. etal. Abnormal bundling and
accumulation of F‑actin mediates tau‑induced
neuronal degeneration invivo. Nat. Cell Biol. 9,
139–148 (2007).
94. Iqbal, K. etal. Defective brain microtubule
assembly in Alzheimer’s disease. Lancet 2,
421–426 (1986).
95. Terry, R.D. The pathogenesis of Alzheimer
disease: an alternative to the amyloid
hypothesis. J. Neuropathol. Exp. Neurol. 55,
1023–1025 (1996).
96. Praprotnik, D., Smith, M.A., Richey, P.L.,
Vinters,H.V. & Perry, G. Filament heterogeneity
within the dystrophic neurites of senile plaques
suggests blockage of fast axonal transport in
Alzheimer’s disease. Acta Neuropathol. 91,
226–235 (1996).
97. Stokin, G.B. & Goldstein, L.S. Axonal transport
and Alzheimer’s disease. Ann. Rev. Biochem. 75,
607–627 (2006).
98. Stieber, A., Mourelatos, Z. & Gonatas, N.K. In
Alzheimer’s disease the Golgi apparatus of a
population of neurons without neurofibrillary
tangles is fragmented and atrophic. Am. J.
Pathol. 148, 415–426 (1996).
99. Lazarov, O. etal. Impairments in fast axonal
transport and motor neuron deficits in
transgenic mice expressing familial Alzheimer’s
disease‑linked mutant presenilin 1. J. Neurosci.
27, 7011–7020 (2007).
100. Pigino, G., Pelsman, A., Mori, H. & Busciglio, J.
Presenilin‑1 mutations reduce cytoskeletal
association, deregulate neurite growth, and
potentiate neuronal dystrophy and tau
phosphorylation. J. Neurosci. 21, 834–842
(2001).
101. Rodrigues, E.M., Weissmiller, A.M. &
Goldstein,L.S. Enhanced β‑secretase
processing alters APP axonal transport and
leads to axonal defects. Hum. Mol. Genet.
http://dx.doi.org/10.1093/hmg/dds297.
102. Tesseur, I. etal. Prominent axonopathy and
disruption of axonal transport in transgenic mice
expressing human apolipoprotein E4 in neurons
of brain and spinal cord. Am. J. Pathol. 157,
1495–1510 (2000).
103. Braak, H., Thal, D.R., Ghebremedhin, E. &
DelTredici, K. Stages of the pathologic process
in Alzheimer disease: age categories from 1 to
100years. J. Neuropathol. Exp. Neurol. 70,
960–969 (2011).
104. Ma, X.M. & Blenis, J. Molecular mechanisms of
mTOR‑mediated translational control. Nat. Rev.
Mol. Cell Biol. 10, 307–318 (2009).
105. Seifert, U. etal. Immunoproteasomes preserve
protein homeostasis upon interferon‑induced
oxidative stress. Cell 142, 613–624 (2010).
106. Gavilan, M.P. etal. Molecular and cellular
characterization of the age‑related
neuroinflammatory processes occurring in
normal rat hippocampus: potential relation with
the loss of somatostatin GABAergic neurons.
J.Neurochem. 103, 984–996 (2007).
107. Pintado, C. etal. Lipopolysaccharide‑induced
neuroinflammation leads to the accumulation of
ubiquitinated proteins and increases
susceptibility to neurodegeneration induced by
proteasome inhibition in rat hippocampus.
J.Neuroinflammation 9, 87 (2012).
108. Forloni, G., Demicheli, F., Giorgi, S., Bendotti, C.
& Angeretti, N. Expression of amyloid precursor
protein mRNAs in endothelial, neuronal and glial
cells: modulation by interleukin‑1. Brain Res.
Mol. Brain Res. 16, 128–134 (1992).
109. Sheng, J.G. etal. Lipopolysaccharide‑induced‑
neuroinflammation increases intracellular
accumulation of amyloid precursor protein and
amyloid β peptide in APPswe transgenic mice.
Neurobiol. Dis. 14, 133–145 (2003).
110. Griffin, W.S. etal. Microglial interleukin‑1 alpha
expression in human head injury: correlations
with neuronal and neuritic beta‑amyloid
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 9
34
|
JANUARY 2013
|
VOLUME 9 www.nature.com/nrneurol
precursor protein expression. Neurosci. Lett.
176, 133–136 (1994).
111. Itoh, T. etal. Expression of amyloid precursor
protein after rat traumatic brain injury. Neurol.
Res. 31, 103–109 (2009).
112. Johnson, V.E., Stewart, W. & Smith, D.H.
Widespread tau and amyloid‑beta pathology
many years after a single traumatic brain injury
in humans. Brain Pathol. 22, 142–149 (2012).
113. Mouzon, B.C. etal. Repetitive mild traumatic
brain injury in a mouse model produces learning
and memory deficits accompanied by
histological changes. J. Neurotrauma
http://dx.doi.org/10.1089/neu.2012.2498.
114. Groemer, T.W. etal. Amyloid precursor protein is
trafficked and secreted via synaptic vesicles.
PLoS ONE 6, e18754 (2011).
115. Koo, E.H. etal. Precursor of amyloid protein in
Alzheimer disease undergoes fast anterograde
axonal transport. Proc. Natl Acad. Sci. USA 87,
1561–1565 (1990).
116. Morales‑Corraliza, J. etal. Invivo turnover of tau
and APP metabolites in the brains of wild‑type
and Tg2576 mice: greater stability of sAPP in the
β‑amyloid depositing mice. PLoS ONE 4, e7134
(2009).
117. Ichihara, N. etal. Axonal degeneration promotes
abnormal accumulation of amyloid β‑protein in
ascending gracile tract of gracile axonal dystrophy
(GAD) mouse. Brain Res. 695, 173–178 (1995).
118. Lee, S., Sato, Y. & Nixon, R.A. Lysosomal
proteolysis inhibition selectively disrupts axonal
transport of degradative organelles and causes
an Alzheimer’s‑like axonal dystrophy. J. Neurosci.
31, 7817–7830 (2011).
119. Weyer, S.W. etal. APP and APLP2 are essential
at PNS and CNS synapses for transmission,
spatial learning and LTP. EMBO J. 30,
2266–2280 (2011).
120. Stokin, G.B. etal. Axonopathy and transport
deficits early in the pathogenesis of Alzheimer’s
disease. Science 307, 1282–1288 (2005).
121. Wirths, O., Weis, J., Szczygielski, J., Multhaup, G.
& Bayer, T.A. Axonopathy in an APP/PS1
transgenic mouse model of Alzheimer’s disease.
Acta Neuropathol. 111, 312–319 (2006).
122. Martin, L.J., Pardo, C.A., Cork, L.C. &
Price,D.L. Synaptic pathology and glial
responses to neuronal injury precede the
formation of senile plaques and amyloid
deposits in the aging cerebral cortex. Am. J.
Pathol. 145, 1358–1381 (1994).
123. Yu, W.H. etal. Macroautophagy—a novel
β‑amyloid peptide‑generating pathway activated
in Alzheimer’s disease. J. Cell. Biol. 171, 87–98
(2005).
124. Cataldo, A.M. & Nixon, R.A. Enzymatically active
lysosomal proteases are associated with
amyloid deposits in Alzheimer brain. Proc. Natl
Acad. Sci. USA 87, 3861–3865 (1990).
125. Schechter, I. & Ziv, E. Cathepsins S, B and L
with aminopeptidases display β‑secretase
activity associated with the pathogenesis of
Alzheimer’s disease. Biol. Chem. 392, 555–569
(2011).
126. Jin, M. etal. Soluble amyloid β‑protein dimers
isolated from Alzheimer cortex directly induce
tau hyperphosphorylation and neuritic
degeneration. Proc. Natl Acad. Sci. USA 108,
5819–5824 (2011).
127. Brecht, W.J. etal. Neuron‑specific
apolipoproteinE4 proteolysis is associated with
increased tau phosphorylation in brains of
transgenic mice. J.Neurosci. 24, 2527–2534
(2004).
128. Zhou, W., Scott, S.A., Shelton, S.B. &
Crutcher,K.A. Cathepsin D‑mediated proteolysis
of apolipoprotein E: possible role in Alzheimer’s
disease. Neuroscience 143, 689–701 (2006).
129. Adalbert, R. etal. Severely dystrophic axons at
amyloid plaques remain continuous and
connected to viable cell bodies. Brain 132,
402–416 (2009).
130. Scheff, S.W., Price, D.A., Schmitt, F.A. &
Mufson, E.J. Hippocampal synaptic loss in early
Alzheimer’s disease and mild cognitive
impairment. Neurobiol. Aging 27, 1372–1384
(2006).
131. Misko, A.L., Sasaki, Y., Tuck, E., Milbrandt, J. &
Baloh, R.H. Mitofusin2 mutations disrupt axonal
mitochondrial positioning and promote axon
degeneration. J. Neurosci. 32, 4145–4155
(2012).
132. Ittner, L.M. & Gotz, J. Amyloid‑β and tau—a toxic
pas de deux in Alzheimer’s disease. Nat. Rev.
Neurosci. 12, 65–72 (2011).
133. Yilmazer‑Hanke, D.M. & Hanke, J. Progression of
Alzheimer‑related neuritic plaque pathology in
the entorhinal region, perirhinal cortex and
hippocampal formation. Dement. Geriatr. Cogn.
Disord. 10, 70–76 (1999).
134. Schmidt, M.L., DiDario, A.G., Lee, V.M. &
Trojanowski, J.Q. An extensive network of PHF
tau‑rich dystrophic neurites permeates
neocortex and nearly all neuritic and diffuse
amyloid plaques in Alzheimer disease. FEBS
Lett. 344, 69–73 (1994).
135. de Calignon, A. etal. Caspase activation
precedes and leads to tangles. Nature 464,
1201–1204 (2010).
136. Buki, A., Okonkwo, D.O., Wang, K.K. &
Povlishock, J.T. Cytochromec release and
caspase activation in traumatic axonal injury.
J.Neurosci. 20, 2825–2834 (2000).
137. Rohn, T.T. etal. Caspase‑9 activation and caspase
cleavage of tau in the Alzheimer’s disease brain.
Neurobiol. Dis. 11, 341–354 (2002).
138. Leroy, K. etal. Early axonopathy preceding
neurofibrillary tangles in mutant tau transgenic
mice. Am. J. Pathol. 171, 976–992 (2007).
Acknowledgements
This study was supported by the Swiss National
Science Foundation, grant number 310030‑132629,
the Gottfried und Julia Bangerter‑Rhyner Foundation,
and the Olga Mayenfisch Foundation.
Author contributions
Both authors contributed to researching data for the
article, discussions of the content, writing the article
and to review and/or editing of the manuscript
beforesubmission.
REVIEWS
© 2013 Macmillan Publishers Limited. All rights reserved
Page 10
  • Source
    • "Obesityassociated inflammation, for example, appears to help to maintain insulin sensitivity, therefore it has also been postulated that anti-inflammatory therapies have failed in the treatment of insulin resistance [35], since inflammation promotes energy expenditure in a feedback manner to counteract an energy surplus to regulate energy balance [123], whereas in peripheral tissues induces it fat mobilization and oxidation to promote energy expenditure. In fact this broader (dys)regulation of energy in the context of chronic inflammatory diseases (such as rheumatoid arthritis) has been beautifully articulated by Straub in a series of papers exploring the systemic implications of chronic inflammation [102,[105][106][107][108]. Considering the major challenges of the future, it has already been recognized that diseases such as Alzheimer's and cancer have strong systemic components acting as either a pre-disposing factor or contributing to the development of the disease [60, 61, 80, 88]. The systemic nature of cancer is not a recent realization [79]; however, we may now have the opportunity to materialize such ideas for the benefit of drug discovery, disease treatment, and improvement of health, by understanding the systemic aspect of the response mechanisms , their interactions with low-level targets and their reciprocal engagement and activation. "
    [Show abstract] [Hide abstract] ABSTRACT: Quantitative Systems Pharmacology (QSP) is receiving increased attention. As the momentum builds and the expectations grow it is important to (re)assess and formalize the basic concepts and approaches. In this short review, I argue that QSP, in addition to enabling the rational integration of data and development of complex models, maybe more importantly, provides the foundations for developing an integrated framework for the assessment of drugs and their impact on disease within a broader context expanding the envelope to account in great detail for physiology, environment, and prior history. I articulate some of the critical enablers, major obstacles, and exciting opportunities manifesting themselves along the way. Charting such overarching themes will enable practitioners to identify major and defining factors as the field progressively moves towards personalized and precision healthcare delivery.
    Preview · Article · Apr 2016
  • Source
    • "Salient features of AD include molecular aberrations such as oxidative stress [8], inflammation [32]. Of these features, oxidative stress appears to be the trigger of free radicalinduced cellular damage, DNA oxidation, and aberration in DNA repair [33]. "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder and its reported pathophysiological features in the brain include the deposition of amyloid beta peptide, chronic inflammation, and cognitive impairment. The incidence of AD is increasing worldwide and researchers have studied various aspects of AD pathophysiology in order to improve our understanding of the disease. Thus far, the onset mechanisms and means of preventing AD are completely unknown. Peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) is a protein related to various cellular mechanisms that lead to the alteration of downstream gene regulation. It has been reported that PGC-1α could protect cells against oxidative stress and reduce mitochondrial dysfunction. Moreover, it has been demonstrated to have a regulatory role in inflammatory signaling and insulin sensitivity related to cognitive function. Here, we present further evidence of the involvement of PGC-1α in AD pathogenesis. Clarifying the relationship between PGC-1α and AD pathology might highlight PGC-1α as a possible target for therapeutic intervention in AD.
    Full-text · Article · Mar 2016 · Anatomy & cell biology
  • Source
    • "Furthermore, daily supplementation with high-DHA (1700 mg DHA and 600 mg EPA) for six months in AD patients (OmegAD study) reduced the levels of lipopolysaccharide (LPS)-induced cytokines (IL-1B, IL-6) released from isolated PBMCs relative to within-patient baseline levels [307]. During pathological aging of the brain (and even in some cognitively normal elderly), inflammation results in neurofibrillary tangles made of abnormal forms of tau protein that cause alterations in cytoskeletal stability, axonal transport, and loss of synaptic contacts [269,300]. This can affect protein extrusion mechanisms and axonal energy metabolism, resulting in even more phosphorylated tau (p-tau), axonal blockage and leakage, and ultimately cell death. "
    [Show abstract] [Hide abstract] ABSTRACT: Docosahexaenoic acid (DHA) is the predominant omega-3 (n-3) polyunsaturated fatty acid (PUFA) found in the brain and can affect neurological function by modulating signal transduction pathways, neurotransmission, neurogenesis, myelination, membrane receptor function, synaptic plasticity, neuroinflammation, membrane integrity and membrane organization. DHA is rapidly accumulated in the brain during gestation and early infancy, and the availability of DHA via transfer from maternal stores impacts the degree of DHA incorporation into neural tissues. The consumption of DHA leads to many positive physiological and behavioral effects, including those on cognition. Advanced cognitive function is uniquely human, and the optimal development and aging of cognitive abilities has profound impacts on quality of life, productivity, and advancement of society in general. However, the modern diet typically lacks appreciable amounts of DHA. Therefore, in modern populations, maintaining optimal levels of DHA in the brain throughout the lifespan likely requires obtaining preformed DHA via dietary or supplemental sources. In this review, we examine the role of DHA in optimal cognition during development, adulthood, and aging with a focus on human evidence and putative mechanisms of action.
    Full-text · Article · Feb 2016 · Nutrients
Show more