UCLA
UCLA Previously Published Works
Title
Neuroinflammation in Alzheimer's disease.
Permalink
https://escholarship.org/uc/item/99h2f9m1
Journal
The Lancet. Neurology, 14(4)
ISSN
1474-4422
Authors
Heneka, Michael T
Carson, Monica J
El Khoury, Joseph
et al.
Publication Date
2015-04-01
DOI
10.1016/s1474-4422(15)70016-5
Peer reviewed
eScholarship.org Powered by the California Digital Library
University of California
388
www.thelancet.com/neurology Vol 14 April 2015
Review
Lancet Neurol 2015; 14: 388–405
Department of Neurology,
University Hospital Bonn,
University of Bonn, Bonn,
Germany (Prof M
T Heneka MD,
Prof G
C Petzold MD,
M P Kummer PhD); German
Center for Neurodegnerative
Diseases (DZNE), Bonn,
Germany (Prof M T Heneka,
F Brosseron PhD, Prof E Latz MD,
Prof G C Petzold); Division of
Biomedical Sciences, Center for
Glial-Neuronal Interactions,
University of California,
Riverside, CA, USA
(Prof M J Carson PhD); Division
of Infectious Diseases,
Massachusetts General
Hospital, Harvard Medical
School, Charlestown, MA, USA
(Prof J El Khoury MD); Alzheimer
Research Laboratory,
Department of Neurosciences,
Case Western Reserve
University School of Medicine,
Cleveland, OH, USA
(Prof G E Landreth PhD);
Department of Anesthesiology,
University of Illinois, Chicago,
IL, USA (Prof D L Feinstein PhD);
Department of Geriatrics,
Johanniter Hospital, Bonn,
Germany (Prof A H Jacobs MD);
European Institute for
Molecular Imaging (EIMI) at
the Westfalian Wilhelms
University (WWU), Münster,
Germany (Prof A H Jacobs);
Department of Neurology and
Neurological Sciences, Stanford
University School of Medicine,
Stanford, CA, USA
(Prof T Wyss-Coray PhD); Center
for Tissue Regeneration, Repair,
and Restoration, VA Palo Alto
Health Care System, Palo Alto,
CA, USA (Prof T Wyss-Coray);
Instituto de Biomedicina de
Sevilla (IBIS), Hospital
Universitario Virgen del Rocio,
Consejo Superior de
Investigaciones Cientifi cas
Universidad de Sevilla, Sevilla,
Spain (Prof J Vitorica PhD);
Department of Neuroscience,
Neuroinfl ammation Research
Center, Lerner Research
Institute, Cleveland Clinic,
Cleveland, OH, USA
(Prof R M Ransohoff MD);
Neuroinfl ammation in Alzheimer’s disease
Michael T Heneka, Monica J Carson, Joseph El Khoury, Gary E Landreth, Frederic Brosseron, Douglas L Feinstein, Andreas H Jacobs,
Tony Wyss-Coray, Javier Vitorica, Richard M Ransohoff , Karl Herrup, Sally A Frautschy, Bente Finsen, Guy C Brown, Alexei Verkhratsky,
Koji Yamanaka, Jari Koistinaho, Eicke Latz, Annett Halle, Gabor C Petzold, Terrence Town, Dave Morgan, Mari L Shinohara, V Hugh Perry,
Clive Holmes, Nicolas G Bazan, David J Brooks, Stéphane Hunot, Bertrand Joseph, Nikolaus Deigendesch, Olga Garaschuk, Erik Boddeke,
Charles A Dinarello, John C Breitner, Greg M Cole, Douglas T Golenbock, Markus P Kummer
Increasing evidence suggests that Alzheimer’s disease pathogenesis is not restricted to the neuronal compartment,
but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins
bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised
by release of infl ammatory mediators, which contribute to disease progression and severity. Genome-wide analysis
suggests that several genes that increase the risk for sporadic Alzheimer’s disease encode factors that regulate glial
clearance of misfolded proteins and the infl ammatory reaction. External factors, including systemic infl ammation
and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression.
Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive
strategies for Alzheimer’s disease.
Introduction
At fi rst glance, the specialties of immunology and
neurobiology could not be more diff erent. From a
cellular perspective, the brain represents stasis, whereas
the immune system represents motion. But these two
perspectives have come together as eff orts to understand
the pathogenesis of neurodegenerative disease have
borne fruit. Emerging evidence suggests that
infl ammation has a causal role in disease pathogenesis,
and understanding and control of interactions between
the immune system and the nervous system might be
key to the prevention or delay of most late-onset CNS
diseases. In Alzheimer’s disease, neuroinfl ammation is
not a passive system activated by emerging senile
plaques and neurofi brillar tangles, but instead
contributes as much (or more) to pathogenesis as do
plaques and tangles themselves.
1
The important role of
neuroinfl ammation is supported by fi ndings that genes
for immune receptors, including TREM2
2
and CD33,
3,4
are associated with Alzheimer’s disease. Analysis of
clinical manifestations that precede the dementia stage
of Alzheimer’s disease, such as mild cognitive
impairment, further support an early and substantial
involvement of infl ammation in disease pathogenesis.
In this Review we provide an overview of the
neuroinfl ammatory landscape during Alzheimer’s
disease, including associated cell types and mediators,
methods used to visualise neuroinfl ammation, and its
clinical presentation and potential treatments.
Cellular players
Microglia
Microglia, the resident phagocytes of the CNS, are
ubiquitously distributed in the brain. Microglia
constantly use highly motile processes to survey their
assigned brain regions for the presence of pathogens and
cellular debris, and simultaneously provide factors that
support tissue maintenance (fi gure 1).
5
At the same time,
microglia are important players in the maintenance and
plasticity of neuronal circuits, contributing to the
protection and remodelling of synapses.
6
To some extent,
this protective and remodelling action is mediated by
release of trophic factors, including brain-derived
neurotrophic factor, which contributes to memory
formation.
7
Once activated by pathological triggers, such
as neuronal death or protein aggregates, microglia extend
their processes to the site of injury, and migrate to the
lesion, where they initiate an innate immune response
(fi
gure 2). Detection of pathological triggers is mediated
by receptors that recognise danger-associated molecular
patterns (DAMPs) or pathogen-associated molecular
patterns (PAMPs). In Alzheimer’s disease, microglia are
able to bind to soluble amyloid β (Aβ) oligomers and Aβ
fi
brils via cell-surface receptors, including SCARA1,
CD36, CD14, α6β1 integrin, CD47, and Toll-like receptors
(TLR2, TLR4, TLR6, and TLR9),
8–11
and this process is
thought to be part of the infl ammatory reaction in
Alzheimer’s disease. The Aβ peptide is derived from
amyloid precursor protein (APP) by sequential cleavages
by two membrane-bound proteases (fi gure 3).
12,13
The
42-aminoacid form of Aβ has a particularly strong
tendency to form soluble oligomers and fi brils. Binding
of Aβ with CD36, TLR4, and TLR6 results in activation of
microglia, which start to produce proinfl ammatory
cytokines and chemokines (fi gure 4).
10,14
In turn, genetic
deletion of CD36, TLR4, or TLR6 in vitro reduces Aβ-
induced cytokine production
10,14,15
and prevents
intracellular amyloid accumulation and activation of
multiprotein complexes known as infl ammasomes.
15
Microglial Aβ clearance mechanisms
In response to receptor ligation, microglia start to engulf
Aβ fi brils by phagocytosis. As a result, these fi brils enter
the endolysosomal pathway. By contrast with fi brillar Aβ,
which is mostly resistant to enzymatic degradation,
soluble Aβ can be degraded by various extracellular
proteases.
16
In microglia, the proteases neprilysin and
insulin-degrading enzyme (IDE) are of major importance.
www.thelancet.com/neurology Vol 14 April 2015
389
Review
Division of Life Science, Hong
Kong University of Science and
Technology, Hong Kong
(Prof K Herrup PhD);
Department of Neurology,
David Geff en School of
Medicine at the University of
California, Los Angeles, the
Geriatric, Research, and Clinical
Center, Greater Los Angeles
Veterans Aff airs Healthcare
System, Los Angeles, CA, USA
(Prof S A Frautschy PhD,
Prof G M Cole PhD); Institute of
Molecular Medicine, University
of Southern Denmark, Odense,
Denmark (Prof B Finsen MD);
Department of Biochemistry,
University of Cambridge,
Cambridge, UK
(Prof G C Brown PhD); Faculty of
Life Sciences, The University of
Manchester, Manchester, UK
(Prof A Verkhratsky MD);
Achucarro Center for
Neuroscience, Basque
Foundation for Science
In sporadic cases of Alzheimer’s disease, ineffi cient
clearance of Aβ has been identifi ed as a major
pathogenic pathway.
17
Increased cytokine concentrations,
by downregulation of expression of Aβ phagocytosis
receptors, are suggested to be responsible for
insuffi cient microglial phagocytic capacity.
18
Further
support for the hypothesis of compromised microglial
function is provided by two studies
2,3
identifying rare
mutations that convey an increased risk of Alzheimer’s
disease. A rare mutation in the extracellular domain of
TREM2 increases risk of Alzheimer’s disease to a
similar extent to apolipoprotein E (ApoE) ε4.
2
TREM2 is
highly expressed by microglia,
19,20
and mediates
phagocytic clearance of neuronal debris.
21
Although a
TREM2 ligand has not yet been discovered, TREM2
binding activity (putative TREM2 ligand expression) is
detected on reactive astrocytes surrounding amyloid
plaques and on damaged neurons and oligodendrocytes.
21
Likewise, a single-nucleotide poly morphism (SNP) in
the gene encoding the microglial surface receptor CD33
reduces Aβ phagocytosis by peripheral macrophages
isolated from heterozygous and homozygous mutation
carriers. Additionally, increased Aβ deposition, as
shown by Pittsburgh compound B (PiB)-PET, was
detected in the brains of carriers of the rs3865444 allele
in the CD33 Alzheimer’s disease susceptibility locus.
3
Microglial diversity
Microglia activation is a complex process that results in
several phenotypes. Outside the CNS, activated
macrophages have been categorised as those with a
classic, proinfl ammatory (M1) phenotype associated with
expression of cytotoxic genes,
22
and those with a non-
infl ammatory, alternative activation (M2) phenotype,
associated with induction of specifi c proteins, including
ARG1, FIZZ1, YM1, and IGF1.
23,24
Classic M1 activation is
characterised by increased concentrations of pro-
infl ammatory cytokines, including TNFα, interleukin 1,
interleukin 6, interleukin 12, and interleukin 18, and is
accompanied by impaired phagocytic capacity.
25
The M2
state is characterised by secretion of the anti-
infl ammatory cytokines interleukin 4, interleukin 10,
interleukin 13, and TGF-β, and increased phagocytic
capacity without production of toxic nitric oxide.
26–28
A
third phenotype might be a deactivated one associated
with corticosteroids or TGF-β.
29,30
The M1 and M2
activation states represent the extremes of myeloid cell
activation. Peripheral monocyte-derived macrophages
exist in a diverse range of phenotypic states, particularly
under conditions of chronic infl ammation.
31
Microglia
are also likely to exist in a range of phenotypic states
during chronic infl ammation: these cells have a wide
range of phenotypes that are indicative of their response
to the local environment, including physical interaction
with other cells and their physiological activity in the
brain. Importantly, the ability to isolate or image subsets
of unperturbed microglia to characterise their gene
expression and mode of action as discriminated by
physiological markers is restricted at present.
Microglia priming
In the ageing CNS of mice, rats, and primates, microglia
show enhanced sensitivity to infl ammatory stimuli,
32
similar to that noted in microglia in brains with ongoing
neurodegeneration. This phenomenon is termed
priming. Priming might be caused by microglial
senescence and might be associated with ageing. On the
transcriptomic level, endogenous ligands are
downregulated during ageing, whereas factors for host
defence and neuroprotection are upregulated.
20
To what
extent age-related microglia priming results from cell-
autonomous cellular ageing, rather than prolonged
exposure to the aged neural environment, is uncertain.
In physiologically aged and senescence-accelerated
mice, profound microglia priming was characterised by
increased production of cytokines and reactive oxygen
species, and enhanced phagocytic capacity. This model
provided proof of principle that environmental eff ects,
such as neuronal ageing, can drive microglia priming.
Figure 1: Pathomechanistic sequelae of microglia activation
Physiological functions of microglia, including tissue surveillance and synaptic remodelling, are compromised
when microglia sense pathological amyloid β accumulations. Initially, the acute infl ammatory response is thought
to aid clearance and restore tissue homoeostasis. Triggers and aggravators promote sustained exposure and
immune activation, which ultimately leads to chronic neuroinfl ammation. Perpetuation of microglia activation,
persistent exposure to proinfl ammatory cytokines, and microglial process retraction cause functional and
structural changes that result in neuronal degeneration. TLR=Toll-like receptor.
Microglia
Clearance and
resolution
Physiological microglial
surveillance, synaptic
remodelling
Innate immune
response
Chronic inflammation
Neurodegeneration
Cytokines,
chemokines
Early microglial
reaction, TLR binding
Activation of microglia
by amyloid β deposits
Reduced synaptic
remodelling
Neuronal death
Triggers
Pathological ageing,
trauma, locus coeruleus
degeneration,
genetic mutations
Aggravators
Peripheral inflammation,
obesity, reduced
microbial diversity
Effects
Functional and structural
damage to neurons,
perpetuation of
inflammation by
neuronal debris
390
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Review
Weighted gene correlation network analysis revealed a
characteristic pattern of gene expression for microglia
priming, featuring increased pattern recognition and
expression of interferon signalling genes. A similar
gene expression network was reported in mouse models
of age-related neurodegeneration, including APP/PS1
transgenic mice.
33
Microglia might also be primed by
systemic infl ammation in response to peripheral
immune reaction.
Modulation of microglia
The emerging role of microglia activation in Alzheimer’s
disease pathogenesis makes these cells a legitimate
therapeutic target. However, depending on the
circumstances, microglia activation can have both
benefi cial and detrimental eff ects. Thus, microglia
might have diff erent roles and eff ects depending on the
particular disease stage and which brain region is
aff ected in each model. After exposure to a DAMP or
PAMP, the acute microglial reaction aims to remove the
recognised abnormality or pathological change. In the
case of Alzheimer’s disease, this type of infl ammatory
reaction is sterile because it involves the same receptors
but no living pathogens. Under normal circumstances,
such a reaction quickly resolves pathological changes
with immediate benefi t to the nearby environment.
However, in Alzheimer’s disease, several mechanisms,
including ongoing formation of Aβ and positive-
feedback loops between infl ammation and APP
processing, compromise cessation of infl ammation.
Instead, further accumulation of Aβ, neuronal debris,
and, most probably, further activating factors establish
chronic, non-resolving infl ammation. Sustained
exposure to Aβ, chemokines, cytokines, and other
infl ammatory mediators seems to be responsible for the
persistent functional impairment of microglial cells
seen at plaque sites.
40,41
As an intracellular regulator of
microglial function, expression of the autophagy protein
Beclin 1 is reduced in the brains of patients with
Alzheimer’s disease.
42
Beclin 1 has a role in retromer-
mediated sorting of cellular components, including
TREM2, APP, BACE1, and CD36, in the endolysosomal
pathway. Reduction of Beclin 1 expression in vitro and
in vivo interferes with effi cient phagocytosis, resulting
in decreased receptor recycling of CD36 and TREM2,
42
but more receptors might be aff ected.
Plasticity of the microglial phenotype is of fundamental
importance, since resolution of infl ammation clearly
involves conversion to an alternative (ie, similar to M2)
activation state associated with tissue repair, phagocytosis,
and anti-infl ammatory actions. Conversion of microglia
from detrimental to benefi cial players might be achieved
by modulation of proinfl ammatory signalling pathways
such as the NLRP3 infl ammasome. Successful modi-
fi cation of these pathways, however, necessitates that
they are exclusively restricted to microglia and do not
have crucial functions in other cell types. Pharma-
cologically, transition to an alternative activation state
could be achieved through the heterodimeric type II
nuclear receptors PPARγ/RXR, PPARδ/RXR, and
LXR/RXR. Agonists of these receptors are robustly anti-
infl ammatory and stimulate phagocytosis through
induction of CD36, leading to increased microglial Aβ
uptake.
43
Another target is the RXR itself, which might
have a positive eff ect on both LXR-controlled and PPARγ-
controlled genes. Agonism of RXR by bexarotene has
been shown to cause rapid reduction of soluble Aβ,
plaque load, and behavioural defi cits by ApoE-dependent
clearance of Aβ.
44
Nevertheless, results of this study
could not be wholly reproduced by others.
45–48
Although
aberrant and ineff ective activation of microglia has been
fairly well documented for prodromal Alzheimer’s
disease and moderate Alzheimer’s disease, late-stage
eff ects are less well understood. Some evidence exists of
focal micro glial senescence, especially surrounding
neurofi brillary tangles.
40
Blood-derived mononuclear cells
The precise contribution of blood-derived mononuclear
cells infi ltrating the CNS in Alzheimer’s disease, such as
innate immune responses of the brain, is so far unclear,
and knowledge is restricted to animal studies. Results of
(IKERBASQUE), Bilbao, Spain
(Prof A Verkhratsky);
Department of Neurosciences,
University of the Basque
Country UPV/EHU (Euskal
Herriko Unibertsitatea/
Universidad del País Vasco) and
CIBERNED (Centro de
Investigación Biomédica en
Red sobre Enfermedades
Neurodegenerativas), Leioa,
Spain (Prof A Verkhratsky);
Research Institute of
Environmental Medicine,
Nagoya University/RIKEN Brain
Science Institute, Wako-shi,
Japan (Prof K Yamanaka MD);
Department of Neurobiology,
AI Virtanen Institute for
Molecular Sciences, University
of Eastern Finland, Kuopio,
Finland (Prof J Koistinaho MD);
Institute of Innate Immunity,
University of Bonn, Bonn,
Germany (Prof E Latz);
Department of Infectious
Diseases and Immunology,
University of Massachusetts
Medical School, Worcester, MA,
USA (Prof E Latz,
Prof D T Golenbock MD);
Max-Planck Research Group
Neuroimmunology, Center of
Advanced European Studies
and Research (CAESAR), Bonn,
Germany (A Halle MD); Zilkha
Neurogenetic Institute, Keck
School of Medicine of the
University of Southern
California, Los Angeles, CA,
USA (Prof T Town PhD);
Department of Molecular
Pharmacology and Physiology,
Byrd Alzheimer’s Institute,
University of South Florida
College of Medicine, Tampa, FL,
USA (Prof D Morgan PhD);
Department of Immunology,
Duke University Medical
Center, Durham, NC, USA
(Prof M L Shinohara PhD);
Figure 2: Changes in microglia and astroglia in Alzheimer’s disease
Microglia and astroglia are key players in the infl ammatory response: changes in microglia and astroglia are evident in the post-mortem brains of patients with Alzheimer’s disease and in animal
models of the disorder. (A) CD11b-positive microglia (blue) within an amyloid β (Aβ) deposit (brown) in the parietal cortex of a brain section from a patient with Alzheimer’s disease. (B) Activated,
IBA1-positive microglia (green) at an Aβ plaque site (red) in a brain section from an APP/PS1 transgenic mouse. (C) GFAP-positive astrocytes (blue) surround the site of Aβ deposition (brown) in the
parietal cortex of a brain section from a patient with Alzheimer’s disease. (D) GFAP-positive astrocytes (green) at an Aβ plaque site (red) in a brain section from an APP/PS1 transgenic mouse.
(E) Interleukin-1β-positive microglia (brown) in the frontal cortex of a brain section from a patient with Alzheimer’s disease.
A C EB D
50 μm
50 μm
50 μm100 μm
25 μm
www.thelancet.com/neurology Vol 14 April 2015
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Review
these animal studies have shown infi ltration of
peripheral mononuclear cells associated with amyloid
plaques in mouse models.
34
Further, ablation of CD11b-
positive cells in the APP/PS1 mouse model of
Alzheimer’s disease showed that peripheral
mononuclear phagocytes have an important role to
reduce the build-up of Aβ plaques.
34
Restriction of entry
of blood-derived mononuclear cells into the brain, by
deletion of the chemokine receptor CCR2 in the Tg2576
mouse model, led to increased plaque load,
35
although
the mononuclear cell type was not specifi ed. However,
most of these studies used bone marrow irradiation and
subsequent transplantation with fl uorescent, and
therefore traceable, cells. Irradiation of whole animals is
likely to cause damage to the blood–brain barrier. A
further study in which the brain was shielded, thereby
limiting irradiation to the rest of the body, did not report
any cerebral infi ltration by peripheral macrophages, but
concluded that perivascular macrophages, protected by
shielding of the brain, were able to modulate Aβ
deposition depending on the presence of CCR2.
36
Involvement of perivascular macrophages has also been
shown for removal of Aβ in a mouse model of cerebral
amyloid angiopathy.
37
Nevertheless, recruitment of bone-
marrow-derived cells is almost absent in parabiosis
mouse models, even 12 months after initiation.
38
Notably,
in this context, ablation of microglia in APP/PS1 mice by
the HSV thymidine kinase/ganciclovir system did not
change the amyloid pathology, although 95% of
microglia were lost and blood-derived monocytes were
spared by use of bone-marrow-chimeric mice.
39
This
result suggests that peripheral cells do not participate in
phagocytosis of amyloid plaques, although the
observation time was only 2–4 weeks. These results
provide evidence against a substantial contribution of
blood-derived monocytes, but support the idea that
perivascular macrophages have some eff ect on removal
of CNS Aβ depositions.
Astroglia
Pathological responses of astrocytes include reactive
astrogliosis, a complex, multistage and pathology-
specifi c reaction, whereas remodelling of astrocytes is
generally aimed at neuroprotection and recovery of
injured neural tissue.
49,50
Next to activated microglia,
hypertrophic reactive astrocytes accumulate around
senile plaques and are often seen in post-mortem
human tissue from patients with Alzheimer’s disease,
51
and in animal models of the disorder.
52
Glial cell
activation might occur early in Alzheimer’s disease,
even before Aβ deposition.
53
Reactive astrocytes are
characterised by increased expression of glial fi brillary
acidic protein (GFAP) and signs of functional
impairment;
54
however, astrocytes do not seem to lose
their domain organisation, and no evidence of scar
formation exists (fi gure 2). In animal models of
Alzheimer’s disease, the early response is marked by
astroglial atrophy, which might have far-reaching eff ects
on synaptic connectivity, because astrocytes are central
to the maintenance of synaptic transmission, thereby
contributing to cognitive defi cits.
52,54–57
These signs of
Figure 4: Activation of microglia by amyloid β
Amyloid β (Aβ) aggregates (oligomers) act on several Toll-like receptors on the microglial surface, triggering
reactions of the innate immune system, including production of proinfl ammatory cytokines and chemokines. Aβ
oligomers are internalised by microglia, aided by SCARA1, α6β1 integrins, CD36, and CD47.
Amyloid β
Oligomers
Innate immune response
Amyloid β uptake
SCARA1
α6β1
integrin
CD36
CD47
TLR2
TLR4/CD14
TLR6
TLR9
Figure 3: Amyloidogenic processing of amyloid precursor protein
Amyloid precursor protein (APP) is a type 1 transmembrane protein that is
sequentially cleaved by two aspartate proteases. β-site APP cleaving enzyme 1
(the β-secretase BACE1) cleaves the protein to yield a C-terminal fragment
(β-CTF) and secreted soluble peptide APPβ. β-CTF is then processed by presenilin
1 and 2 (part of the γ-secretase complex) to release the amyloid β peptide. The
process results in diff erentially truncated C-termini, ranging from aminoacid 37
to 42. The 42-aminoacid form (Aβ
1–42
) has a particularly strong tendency to form
soluble oligomers and fi brils. These Aβ aggregates bind to cell-surface receptors
on microglia, inducing an infl ammatory activation that results in the secretion of
proinfl ammatory cytokines, including TNFα and interleukin 1β. In this context, it
has been shown that interleukin 1β aggragvates plaque formation by
modulation of APP expression. Additionally, expression of BACE1 is upregulated
by some cytokines, resulting in increased production of Aβ species.
School of Biological Sciences,
Southampton General
Hospital, Southampton, UK
(Prof V H Perry PhD); Clinical
and Experimental Science,
University of Southampton,
Southampton, UK
(Prof C Holmes PhD); Memory
Assessment and Research
Centre, Moorgreen Hospital,
Southern Health Foundation
Trust, Southampton, UK
(Prof C Holmes); Louisiana State
University Neuroscience Center
of Excellence, Louisiana State
University Health Sciences
Center School of Medicine in
New Orleans, LA, USA
(Prof N G Bazan MD); Division of
Experimental Medicine,
Imperial College London,
Hammersmith Hospital,
London, UK
(Prof D J Brooks MD); Centre
National de la Recherche
Scientifi que (CNRS), UMR 7225,
Experimental Therapeutics of
Neurodegeneration, Paris,
France (S Hunot PhD);
Department of Oncology
Pathology, Cancer Centrum
Karolinska, Karolinska
Institutet, Stockholm, Sweden
(Prof B Joseph PhD);
Department of Cellular
Microbiology, Max Planck
Institute for Infection Biology,
Berlin, Germany
N-terminus
APP
C-terminus
β-CTF
Amyloid β Oligomers
Extracellular
Intracellular
BACE1
Presenilin 1 and 2
