In ammation in Alzheimer’s disease and the
in ammation hypothesis
In addition to amyloid beta (Aβ) and tau protein
aggregates, the presence of immune-related antigens and
cells around amyloid plaques in the brains of patients
with Alzheimer’s disease (AD) has been reported since
the 1980s [1-3].  ese initial observations brought about
changes to the previously assumed view of the brain as an
immunologically isolated organ. In the 1990s, additional
fi ndings of activated complement factors, cytokines and a
wide range of related receptors in the brain of AD
patients led to the concept of neuro infl ammation
(infl ammation within the central nervous system (CNS)),
which suggests that immunological processes in the brain
are likely to be involved in the pathology of degenerative
diseases of the CNS. Table 1 lists signs of an altered
immune response reported in AD patients.
 e role of aggregated proteins in the pathology of AD
had to be re-considered to account for these observations.
 e infl ammation hypothesis emerged relatively recently,
when it became clear that the observations of altered
immune processes in AD could not be ignored. Neuro-
infl ammation is still considered to be a downstream
consequence in the amyloid hypothesis, with Aβ amyloid
within the CNS bringing about activation of microglia,
initiating a pro-infl ammatory cascade that results in the
release of potentially neurotoxic substances, including
cytokines, chemokines, reactive oxygen and nitrogen
species, and various proteolytic enzymes, leading to
degenera tive changes in neurons [4-7]. It has also been
suggested that activation of microglia may lead to phos-
phorylation of tau and formation of neurofi brillary
tangles (NFTs) [8-10]. However, the exact role of infl am-
mation in the pathology of AD and its mechanisms in
terms of the cells involved - microglia, astrocytes and
Tlymphocytes - are still debated.
 e infl ammation hypothesis is also supported by
epidemiological retrospective observations that patients
with rheumatoid disease who are on long-term anti-
infl ammatory therapy have a lower prevalence of AD
[11-15]. Other largely observational studies have also
supported the concept that anti-infl ammatory approaches
may be protective against the development of AD [16,17].
Furthermore, transgenic animal studies and human trials
have demonstrated that treatment with nitric oxide-
releasing non-steroidal anti-infl ammatory drugs (NSAIDs)
can reduce and/or prevent the AD pathology (reviewed
by McGeer and McGeer [18]). It has also been shown
that a certain drug with anti-infl ammatory properties
(CNI-1493) suppresses amyloid pathology and improves
memory performance in transgenic mice [19]. Despite
these fi ndings, however, several prospective anti-infl am-
matory strategies against disease progression in subjects
with established AD have failed to show convincingly
positive results (see the ‘Current treatment strategies
based on the infl ammation hypothesis’ section below).
Although these eff ects did not reach signifi cant levels in
large human cohorts [20], interest in the infl ammatory
processes of AD pathology has persisted [21,22]. One
particularly interesting aspect of these studies was that
Abstract
Evidence for the involvement of in ammatory
processes in the pathogenesis of Alzheimer’s disease
(AD) has been documented for a long time. However,
the in ammation hypothesis in relation to AD
pathology has emerged relatively recently. Even in this
hypothesis, the in ammatory reaction is still considered
to be a downstream e ect of the accumulated proteins
(amyloid beta (Aβ) and tau). This review aims to
highlight the importance of the immune processes
involved in AD pathogenesis based on the outcomes
of the two major in ammation-relevant treatment
strategies against AD developed and tested to date
in animal studies and human clinical trials - the use of
anti-in ammatory drugs and immunisation against Aβ.
© 2010 BioMed Central Ltd
In ammation in Alzheimer’s disease: relevance to
pathogenesis and therapy
Elina Zotova*
1
, James AR Nicoll
1,2
, Raj Kalaria
3
, Clive Holmes
1,4
and Delphine Boche
1
REVIEW
*Correspondence: elina.zotova@soton.ac.uk
1
Division of Clinical Neurosciences, School of Medicine, University of
Southampton, Mailpoint 806, Level D, South Pathology Block, Southampton
General Hospital, Southampton, SO16 6YD, UK
Full list of author information is available at the end of the article
Zotova et al. Alzheimer’s Research & Therapy 2010, 2:1
http://alzres.com/2/1/1
© 2010 BioMed Central Ltd

(at least in animal models) the observed benefi cial action
of anti-infl ammatory drugs was not necessarily attributed
to down-regulation of infl ammatory processes. Instead,
activation of microglia via a route that enhances its
phago cytic activity against Aβ was suggested [23].
 e infl ammation hypothesis also suggests another
approach to sporadic AD and associated risk factors for
investigation - polymorphism of genes related to induc tion
and regulation of infl ammatory processes. Initial studies
suggested a role for specifi c cytokine polymorphisms -
for example, in the genes encoding IL-1 and TNFα
[24,25] - with evidence that IL-1 polymorphism may be
associated with diff ering degrees of microglial activation
in AD [26]. However, a meta-analysis of genetic infl u-
ences in AD has not supported the initial fi ndings of
cytokine gene variation as a risk factor for AD, but has
instead emphasised the over-riding importance of the
APOE gene polymorphism as the major genetic risk
factor [27]. Although many mechanisms for the role of
apolipoprotein E (APOE) in AD pathogenesis have been
suggested [28], the key mechanism remains unclear. Of
particular interest to the infl ammation hypothesis is the
fi nding that APOE ε4 carriers with AD have more
marked microglial activation [29].
Research into the role of infl ammation in AD is driven
by questions similar to those posed for Aβ and abnormal
tau accumulation. Can neuroinfl ammation be the cause
of AD? Are the infl ammatory processes in AD contribut-
ing to the disease pathology? Alternatively, are they
merely the consequence of the disease, initiated and
driven by the neurodegeneration? Does infl ammation act
as a harmless bystander in the disease course? Can the
immune processes of the brain be harnessed to fi ght
against the disease pathology?
Infl ammation as the sole cause of AD is usually
considered as unlikely on the basis that peripheral
systemic disorders rarely start with infl ammation - there
is an initial challenge that is required to stimulate an
immune (or infl ammatory) response [30]. However, it
should be noted that being a response to an insult rather
than an insult itself, infl ammation plays an important
role in the reaction of an organism to this insult, with
potentially damaging and sometimes fatal consequences
(for example, in allergy). Autoimmune diseases can aff ect
the CNS (for example, paraneoplastic syndromes,
multiple sclerosis) but there is little evidence to suggest
that AD falls into this category.
With respect to whether infl ammatory processes in AD
contribute to the disease pathology, a lot of evidence has
accumulated suggesting that infl ammation can contribute
to the AD process and exacerbate the course of the
disease. It is still unclear exactly how infl ammation acts
on the diseased brain, as most of the observations about
the mechanisms of its action are based on animal models.
However, the supportive evidence for infl ammation being
a contributor to the disease process is as follows. First,
the cognitive state of AD patients who also have short-
term peripheral infection show signs of sudden decline in
cognitive state, and rarely return to the previous level
even after recovery from the infection [31]. Second,
community-based studies suggest that plasma levels of
infl ammatory proteins, including cytokines, are increased
before clinical onset of dementia, including AD [32],
which may be exacerbated by the presence of athero-
sclerosis [33].  ird, observed signs of infl ammation in
the brain of AD patients are comparable to those seen in
peripheral infl ammatory reactions and are likely to have a
strong cytotoxic eff ect on neurons [5,30]. Fourth, signs of
infl ammation are particularly localised in the brain areas
aff ected by AD pathology and co-localise with plaques
and tau deposits [1,2,34-40]. Fifth, high pathology controls
(individuals who have Aβ and tau aggregates at levels
similar to AD patients, but do not develop dementia)
show lower signs of infl ammation [41]. Sixth, Mini
Table 1. Signs of altered immune response in Alzheimer’s disease patients and relevant references
Signs of altered immune response References
Presence of HLA-DR or LFA-1 (leucocyte function-associated antigen) positive reactive microglia around senile plaques [1,2,35,37,40]
Increased hippocampal gene expression of MHC II in AD compared to high-pathology controls [95]
Elevated brain levels of IL-1β and S-100 [3]
Presence of activated elements of classical complement pathway (C1q, C3d, C4d) within dystrophic neurites, NFTs and/or Aβ plaques [34,36,96]
Up-regulated mRNA levels of complement elements C1q and C9 in AD brain [97]
Strong IL-6 immunoreactivity around plaques and large cortical neurons [38]
Low levels of TNFα in brain areas with AD pathology [39]
Increased levels of TNFα in sera of severe stage AD patients [98]
Increased levels of intracellular neuronal IL10, IFNγ and IL12 in AD patients compared to age-matched controls [99]
Correlations between Mini Mental State Examination scores and in vivo imaging marker [11C](R)PK11195-PET of activated microglia in AD patients [42]
Aβ, amyloid beta; AD, Alzheimer’s disease; IFN, interferon; NFT, neuro brillary tangle.
Zotova et al. Alzheimer’s Research & Therapy 2010, 2:1
http://alzres.com/2/1/1
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