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The role of inflammation in Alzheimer’s disease
The role of inflammation in Alzheimer’s Disease
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The role of inflammation in Alzheimer’s disease
Table of contents
Introduction …………………………………………………………………………3
Alzheimer’s disease …………………………………………………………………4
Pathology of AD …….……………………………………………………….4
Early and Late onset AD .…………………………………………………….5
Clearance of Aβ ……...……………………………………………………….6
Inflammation ………………………………………………………………………...8
General inflammation process ….…………………………………………….8
Inflammation response in AD ……………………………………………….11
Beneficial or harmful? ……………………………………………………….13
Proinflammatory versus anti-inflammatory cytokines ...…………………….15
Aging .………………………………………………………………………………17
Aging of the immune system ..……………………………………………….17
Aging of the Aβ clearance pathways ..……………………………………….18
The transition form normal aging to AD …………………………………….18
Conclusion ..…………………………………………………………………………20
Reference ....…………………………………………………………………………22
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The role of inflammation in Alzheimer’s disease
Introduction
Alzheimer’s disease (AD) was first reported in 1907 by Aloïs Alzheimer. In
the same year, plaques in the brain were described as depositions of a foreign
substance (Fischer, 1907). However, it took almost eighty years before there was
evidence that inflammation related proteins were indeed associated with plaques
(Eikelenboom et al., 2006). Nowadays, AD is the most common neurodegenerative
disease causing progressive impairment of memory and other cognitive functions, in
27 million patients worldwide (Brookmeyer et al., 2007). Current estimates suggest
that the amount of AD patients will triplicate by 2040 (Minati, Edgintio, Bruzzone
and Giaccone, 2009). Unfortunately, there is still no good therapy for AD. To
discover a good treatment for AD it is necessary to understand how different
processes, such as inflammation, are involved in the pathology of AD.
Until today, the exact role of the immune system in the pathology of AD is
unclear. In this thesis the function of the immune system, especially the innate
immune system, will be described and related to AD pathology. It will be discussed
whether the activation of the inflammation process is beneficial or harmful in regard
to the development of AD. Furthermore, this thesis will elucidate the involvement of
aging on the immune system. Francheschi et al. (2007) already have introduced the
term “inflammaging” meaning that the inflammation response changes during aging.
Interestingly, the biggest risk factor for AD is age. Therefore this thesis discuss if the
immune response changes during age and if this can result in the development of AD
pathology.
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The role of inflammation in Alzheimer’s disease
Alzheimer’s disease
Pathology of AD
AD has two pathological hallmarks; extracellular plaques and intracellular
neurofibrillary tangles (NFTs), which eventually lead to neuronal cell loss (Figure 1).
More specifically, NFTs consist of hyperphosphorylated tau, a microtubule stabilizing
protein and plaques consist of accumulated, misfolded ß-amyloid (Aβ). Amyloid
precursor protein (APP) can be cleaved in two different pathways: the nonamyloidogenic pathway and the amyloidogenic pathway. In the non-amyloidogenic
pathway, α-secretase cleaves APP in the middle of the Aβ sequence. In the
amyloidogenic pathway, APP is cleaved by β-secretase (BACE) and γ-secretase.
Depending on the exact cleavage-site of γ-secretase different lengths of the Aβ
peptide are produced namely: Aβ1-39, Aβ1-40 and Aβ1-42 (Uemura, Kuzuya and
Shimohama, 2004).
Figure 1. Pathological hallmarks of AD.
A) Immunohistochemistry with antibody to Aβ showing plaques. B) Immunohistochemistry for
phosphorylated tau showing NFTs. (Minati et al., 2009).
The fact that Aβ is also present in the brain and cerebrospinal fluid (CSF) of
healthy individuals suggests a physiological role of this peptide (Walsh et al., 2000).
Although the exact function of Aβ is indistinct, Giuffrida et al. (2009) demonstrate
that Aβ monomers are neuroprotective by supporting survival of neurons under
conditions of trophic deprivation via activation of the phosphatidylinosiol-3-kinase
pathway (PI-3-K). This result is in line with other research which demonstrates that βand γ-secretase inhibitors result in a decrease of neuronal cell viability (Plant, 2003).
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The role of inflammation in Alzheimer’s disease
However, in AD patients Aβ aggregates from monomer into oligomer, fibrils
and finally into plaques. This accumulation of Aβ is neurotoxic and results in
functional loss of the Aβ peptide. The different Aβ aggregates have a different rate of
toxicity. For a long time it was thought that the insoluble fibrils and plaques were
most toxic, but recently it became clear that the non-fribrillar, soluble forms of Aβ are
more poisonous (Carrotta et al., 2006). This is supported by the fact that the
concentration of soluble Aβ shows a strong correlation with cognitive dysfunction,
while the number of senile plaques is poorly correlated to the severity of the disease
(Kokubo, Kayed, Glabe and Yamaguchi, 2005). Moreover, the soluble oligomers are
the most toxic Aβ species, because oligomers accumulate intracellular at the synaptic
sides which can result in synaptic dysfunction.
Furthermore, there is also a toxicity difference in the isoforms of Aβ. Aβ1-42
is more toxic than the isoforms Aβ1-39 and Aβ1-40. This is probably due to the
increased aggregated characteristic of Aβ1-42. Interestingly, in healthy individuals the
Aβ1-40 isoform is predominant while Aβ1-42 represents only 10% of the total Aβ
whereas in AD patients the relative proportions of these two isoforms are 50% (Mehta
et al., 2001). This ratio difference can be responsible for the increased accumulation
of Aβ in AD.
Different components are involved in the aggregation process from Aβ
monomers into Aβ plaques. First of all, the normal structure of the monomers is a αhelix, but the aggregates have a β-sheet structure. It appears that Aβ monomers
change their α-helix conformation into a β-sheet conformation in physiological pH
and thereby increase their accumulation potential. Nevertheless, the concentration of
Aβ seems to be the most important factor in the accumulation process. A certain
concentration of Aβ peptide is necessary for aggregation, the required concentration is
lower for Aβ1-42 than for Aβ1-40 (Carlo, 2010).
Early and late onset AD
There is a distinction between early and late onset of AD; early onset is
defined as AD before the age of 65 and late onset is defined as AD after the age of 65.
The majority of AD patients consist of individuals with late onset AD (LOAD)
(Williamson, Goldman and Marder, 2009). Early onset AD (EOAD) has been linked
to three established AD genes: presenilin 1 (PSEN1), presenilin 2 (PSEN2) and APP.
The missense mutations in PSEN1 is most frequently observed in EOAD as it
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The role of inflammation in Alzheimer’s disease
accounts for as much as 50% of all cases of EOAD whereas the mutations of PSEN2
are rare (Sherrington et al., 1996). All three mutations lead to increased production of
Aβ and especially to increased production of the Aβ1-42 isoform (Scheuner et al.,
1996).
In relation to LOAD, many genes have been proposed as candidate genes.
Interestingly, many of these genes are not involved in the enhanced production of Aβ,
but rather involved in the clearance of Aβ. For example, polymorphisms in α2macroglobin, apolipoprotein J (ApoJ) and apolipoprotein E (ApoE) are proposed risk
factors to develop LOAD. These genes are chaperone proteins and bind to Aβ to
prevent accumulation and to promote removal (Mettenburg, Webbs and Gonias, 2002;
Wilhemus, Waal and Verbeek, 2007). Recently, genome-wide association studies
have confirmed ApoE as risk factor and have identified two other Aβ associated
proteins clusterin and complement receptor-1 (CR1). Clusterin has a function as
transporter protein in the drainage from Aβ and CR1 is the main receptor of the
complement C3b protein (Harold et al., 2009; Lambert et al., 2009; Seshadri et al.,
2010).
In conclusion, genetic evidence suggests that EOAD is caused by
overproduction of Aβ while LOAD is caused by impairment of Aβ clearance. It is
suggested that an imbalance between Aβ production and Aβ clearance is crucial to
develop AD, because an elevated concentration of Aβ results in accumulation of this
peptide.
Clearance pathways of Aβ
The genetic studies point out the importance of Aβ clearance to prevent Aβ
accumulation. The clearance process of Aβ is complex, because of its many steps and
factors involved in the elimination of Aβ from the brain (Figure 2). First of all, there
are many degrading enzymes which can cleave Aβ at various cleavage sites in vitro.
However, some degrading enzymes are more promising candidates to degraded Aβ in
vivo such as IDE, Neprilysin (NEP) and ACE. Interestingly, the levels of IDE and
NEP are decreased in AD brains compared to age-matched healthy controls, whereas
ACE protein and activity is elevated in AD (Wang, Dickson and Malter, 2006). ACE
could be upregulated to compensate elevated Aβ levels or to compensate decreased
activity of the other degrading enzymes. Further studies are necessary to investigate
the exact function of degrading enzymes during Aβ clearance in AD.
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The role of inflammation in Alzheimer’s disease
Furthermore, Aβ is removed from the brain by transport of Aβ across the
blood-brain barrier (BBB). Subsequently, the liver eliminates part of the Aβ. Besides
normal diffusion, most Aβ efflux is mediated by receptors on endothelial cells. The
most important receptor to transport Aβ out of the brain is the lipoprotein receptorrelated protein (LRP). Surprisingly, expression of LRP is negatively regulated by Aβ
levels, meaning that Aβ clearance across the BBB is decreased when Aβ levels are
increased. In addition, there is an active Aβ influx across the BBB. The most
important receptor involved in this process is the receptor for advanced glycation end
products (RAGE). RAGE is upregulated by elevated Aβ levels in the brain due to a
positive-feedback system (Wang, Zhou and Zhou, 2006). Taken together, increased
Aβ levels in the brain decrease the efflux and increase the influx of Aβ across the
BBB leading to an ineffective removal of Aβ and a further increase of Aβ levels in the
brain.
Another group of proteins involved in the clearance of Aβ are the endogenous
antibodies. These antibodies prevent Aβ aggregation and resolve Aβ fibrils. The antiAβ autoantibodies very low in healthy individuals are found to be even more reduced
in AD patients (Wang, Zhou and Zhou, 2006). This low level of autoantibodies could
contribute to inefficient clearance of Aβ and may result in senile plaques. A different
interesting group of proteins are the chaperones including miscellaneous proteins (e.g.
α2-macroglobin) and apolipoproteins (e.g. ApoE and ApoJ). These proteins can bind
to Aβ and thereby induce conformational changes. The Aβ chaperones contribute to
Aβ clearance by regulating the binding between Aβ and different receptors, both
receptors of the immune system as transport receptors across the BBB (Wilhelmus,
Waal and Verbeek, 2007). For example, LRP-1 binds Aβ in a complex with ApoE
and transports it into the plasma (Shibata et al., 2000). Aβ binding proteins also
contribute to Aβ clearance by preventing aggregation of Aβ, because removal of
soluble Aβ is more efficient than removal of aggregated Aβ (Wilhelmus, Waal and
Verbeek, 2007).
Finally, the immune system plays also a role in the clearance pathway. The
exact role of the immune system in the elimination of Aβ is complex, because it has
not been elucidated yet whether inflammation is beneficial or destructive in respect to
the development of AD.
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The role of inflammation in Alzheimer’s disease
Figure 2. Clearance Pathways of Aβ.
First of all, Aβ can be eliminated by degrading enzymes. Aβ can also passively or actively transported
across the BBB. The LRP receptor transport Aβ out of the brain, but RAGE transport Aβ into the brain.
Both Chaperones and antibodies bind to Aβ and thereby prevent accumulation of the peptide.
Chaperones can also assist between Aβ and certain receptors such as the transporter receptor across the
BBB.
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The role of inflammation in Alzheimer’s disease
Inflammation
General inflammation process
The immune system exists of two components: the innate immune system and
the adaptive immune system. The innate immune system is the first defence against
pathogens or damaged tissue and is aspecific (Figure 3). The adaptive immune system
is the second response and is antigen-specific. Lymphocytes are the most important
cells of the adaptive immune system and eliminate cells with antigens (Murphy,
Travers and Walport, 7th edition).
The most important cells of the innate immune system in the brain are
microglia cells. Although microglial activity is suppressed, the brain is under constant
surveillance of microglia. Whenever a pathogen or injury in the brain is detected,
microglia cells become active and try to remove the foreign tissue (Biber et al., 2007).
Two types of microglia cells are distinguished: the M1 and the M2 phenotype
(Mantovani et al., 2004). The M1 is considered as proinflammatory and M2 as antiinflammatory. A proinflammatory response is known for amplifying the immune
response and for the production of reactive species like reactive oxygen species (ROS)
and nitric oxide (NO), which are produced to kill the pathogen. An anti-inflammatory
response does not amplify the immune response and secretes more trophic factors
(Yong, 2010). Activated microglial cells, as well as other cells, secrete cytokines.
Cytokines are small proteins which induce a local response by binding to receptors,
this local response can either be proinflammatory or anti-inflammatory. Special kinds
of cytokines are chemokines. These chemokines are released early in the infection
phase and induce chemotaxis in nearby cells. Both cytokines and chemokines have an
influence on the function of microglia and other cells of the immune system. In
addition, the clearance capacity of microglia is also effected by the complement
system (lee and landreth, 2010).
The complement system is part of the innate immune system and adaptive
immune system. It can be activated in one of three pathways: it can recognize
antibody-antigen complexes (adaptive immune system) or surface components of
certain pathogens (innate immune system), it can bind to lectin on the pathogen
surface or it can bind to the pathogen by spontaneous hydrolysis of C3. Complement
activation involves a series of cleavage reactions whereby 30 different proteins are
involved. In all three pathways these cleavage reactions result in enzymatic activity of
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The role of inflammation in Alzheimer’s disease
C3 convertase, which cleaves complement component C3 into C3b and C3a. C3a is a
peptide mediator of local inflammation. C3b binds covalently to the pathogen
membrane and opsonises it enabling phagocytes. C3b also activates another series of
cleavage reactions resulting in more cytokines and a membrane-attack complex,
which creates a pore in the cell membrane that can lead to cell death (Beek et al.,
2003). The liver is the major source of complement proteins, but neurons and glial
cells also express complement factors. On the other hand, complement factors and
cytokines, which are activated by complement system, both trigger microglia and
astrocytes (Veerhuis et al., 1999).
Astrocytes, the most frequent cells in the brain have long been considered as
supporting cells for neurons, but nowadays it is clear that astrocytic function goes
beyond neurotrophic support. Astrocytes are involved in many other functions such as
neurotransmission, cell signalling, synapse modulation and, most important,
inflammation. Several cytokines and chemokines act on astrocytes and astrocytes also
produce different kinds of cytokines (Ricci et al., 2009). In fact, it appears that there is
a close interaction between astrocytes and microglia cells. Microglia encourage the
reactive astrocytic phenotype. However, the normally negative feedback of
differentiated astrocytes on microglia disappears when astrocytes become reactive.
This results in an increase of the proinflammatory microglial phenotype and the
production of toxic NO (Schubert, Ogata, Marchini and Ferroni, 2001). Taken
together, astrocytes are an important part of the inflammation response.
Finally, neurons also seem to be involved in the innate immune response.
Neuronal supernatants influence the function of microglia in vitro. Moreover, neurons
secrete chemokines to induce migration of microglia and both neuronal activity and
neurotransmitters inhibit microglial activity (Biber, Neumann, Inoue and Boddeke,
2007).
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The role of inflammation in Alzheimer’s disease
Figure 3. The components of the innate immune response.
Pathogens, damaged tissue and also Aβ accumulation can activate the innate immune response.
Chemokines and cytokines are produced, which activate microglia, the complement system and
astrocytes. Activated microglia can have a proinflammatory or anti-inflammatory phenotype. During
activation of the complement system is C3 cleaved in C3a and C3b. C3a stimulates both activation of
microglia and reactive astrocytes. Finally, microglia and astrocytes have a close interaction:
differentiated astrocytes inhibit the amount of activated microglia, but activated microglia stimulate the
transition from differentiated to reactive astrocytes.
Inflammation response in AD
It is indisputable that inflammation plays a role in AD, because many factors
involved in the immune response are elevated or activated in the AD brain. First of all,
microglia are activated and closely associated with plaques (Perlmutter, Barron and
Chui, 1990; Frauschy et al., 1998). Moreover, microglia migrate to newly formed
plaques within two days and the number and size of microglia is in proportion with
the size of the plaques. (Lee and Landreth, 2010). Next to microglia are also
astrocytes related to AD pathology. Accumulation of reactive astrocytic processes
around and within Aβ plaques have been observed (Nagy, 1996). Interestingly,
astrocytes are also closely related to both fibrillary and diffuse Aβ deposits, whereas
microglia only seem to be associated with Aβ plaques (Benzing et al., 1999). Finally,
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The role of inflammation in Alzheimer’s disease
many of the cytokines, chemokines and components of the complement system are
identified and found to be elevated in the AD brain (Akiyama et al., 2000;
Eikelenboom et al., 1989).
Interestingly, there is evidence that the inflammatory process is an early event
in AD and not necessarily activated after Aβ plaque formation. First of all, in post
mortem brains, a gradual increase of microglia and astrocytes with Braak score
suggests that inflammation is an early event in AD (Hoozemans et al., 2005).
Furthermore, in vivo detection of increased microglial activation in early forms of AD
suggests that microglial activation is an early event in the pathogenesis of the disease
(Cagnin et al., 2001). Moreover, a PET study in patients with mild cognitive
impairment shows activated microglia and Aβ deposits (Okello et al., 2010). This is
interesting since most of the mild cognitive impairment conditions ultimately convert
into AD (Bozoki et al., 2001). In addition, significant increases of microglia activation
have been observed in possible AD cases (defined as individuals with AD deposits but
no dementia). However, there is only increased astrocytic activity observed in definite
AD cases (Vehmas, Kawas, Stewart and Troncoso, 2003). This suggests that
microglia activation is a very early event in the pathology of AD and that astrocytic
activity is a secondary event after microglia activation. An early event in the
pathology of a disease indicates that this event could contribute to the progress of the
disease. Thus, the early activation of the inflammatory process implies that
inflammation plays an important role in AD pathology.
There is indeed evidence that inflammation is important in the pathology of
AD. For instance, cognitive performance of AD patients correlates inversely with
activated microglial density rather than with plaque load, which suggests that
inflammation is a more important component in the progress of AD than the overall
plaque load (Combs, 2009). It is not surprising that plaque load does not correlate
with cognitive performance, because as mentioned above plaques are not the most
toxic species of Aβ. It has even been suggested that plaque formation protects the
brain through removal and inactivation of smaller, neurotoxic species (Finder and
Clockshuber, 2007). Nevertheless, higher serum levels of systemic inflammation
markers also predict cognitive decline and dementia (Eikelenboom et al., 2010).
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The role of inflammation in Alzheimer’s disease
Beneficial or harmful?
Often is spoken of a double-edged sword in respect to the role of inflammation in the
progress of AD. Is the activation of microglia and the inflammation response in AD
neurotoxic or neuroprotective?
The activation of the innate immune system seems to be neuroprotective in
regard to the clearance capacity of this process. For instance, activated microglia
produce and secrete degrading enzymes and can engulf Aβ. However, the idea that
microglia can degrade Aβ is still controversial (Lee and Landreth, 2010). Regardless
of microglia can degraded Aβ, enhanced microglia phagocytosis has proven to be
beneficial in models of AD (Turrin and Rivest, 2006). Moreover, astrocytes have the
ability to form a barrier between Aβ deposits and neurons, which can protect the
neurons from the toxic Aβ species. Astrocytes can also bind, internalize and degrade
Aβ deposits, but astrocytes are less efficient in these processes than microglia (Ricci
et al., 2009). Besides the possible clearance capacity of both microglia and astrocytes,
there is evidence that inhibition of components of the inflammatory response leads to
increased plaque formation. For example, inhibition of the complement factor C3 in
APP mice model results in increased Aβ deposition and vice versa; increased
production of C3 lead to reduced Aβ deposits (Wyss-Coray et al., 2002). Additionally,
El Khoury et al. (2007) demonstrated that absence of the chemokine receptor Ccr2,
which is responsible for the recruitment of microglia, resulted in accelerated and
increased Aβ accumulation and mortality. Simard et al. (2006) also demonstrate that
microglia reduce neurotoxicity of Aβ deposits. It must be noted that in both latter
studies the microglia which actively cleared Aβ are bone marrow derived microglia
and not their resident counterparts. Nevertheless, this research still suggests that
inflammation could be beneficial and neuroprotective due to their clearance capacity.
On the other hand, there are a lot of studies showing that inflammation is a
harmful event in the progression of AD. This is not completely surprising, because
intense activation of the inflammatory system in the brain damages the close
environment due to invasion of microglia and the generation of toxic end products
(Yong, 2010; Minghetti 2005). The secretion of toxic end products is a normal
proinflammatory inflammation response for attacking pathogens. Different studies
have shown that Aβ can induce this type of immune response. For instance, Aβtreated inflammatory cells increase the production of ROS. Moreover, Aβ peptides
can directly activate the nicotinamide adenine dinucleotide phosphage (NADPH)
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The role of inflammation in Alzheimer’s disease
oxidase complex which results in production of large amounts of ROS. Interestingly,
similar to Aβ aggregates produce bacteria β-sheet amyloidogenic aggregates. For that
reason it is possible that Aβ structures are interpreted as invading pathogens that elicit
an aggressive neurotoxic response (Lucin and Wyss-Coray, 2009). Consequently, the
production of ROS and NO could result in neuronal damage in the AD brain due to
the toxicity of these species (Della-Bianca et al., 1999; Abramov, Canevari and
Duchen, 2004). Another mechanism by which ROS can be responsible for AD
pathology is the fact that degrading enzyme activity can be impaired due to oxidative
stress (Smith et al., 1996). In other words, the oxidative stress caused by Aβ might
decrease the clearance process and thereby increase accumulation of Aβ.
In addition, nonsteroidal anti-inflammatory drug (NSAID) treatments suggest
that inhibition of the immune response delays the progression of AD (Stewart et al.,
1997). However, it must be noted that some anti-inflammatory agents inhibit γsecretase activity and β-secretase expression and production (Leung et al., 2009;
Sastre et al., 2003). Thus, the effects of anti-inflammatory drugs could be due to the
direct interference with Aβ production and not caused by inhibition of the immune
response. Nevertheless, there is evidence that chronic inflammation can increase Aβ
production. Combinations of inflammatory cytokines increase secretion of Aβ in
cultured human neuronal cells and astrocytes (Blasko et al., 1999, 2000). In addition,
it is demonstrated that inflammatory cytokine stimulation upregulates the expression
and activity of BACE1 (Sastre et al., 2003). The increased activity of BACE1 after
inflammatory cytokine stimulation could be responsible for the enhanced production
of Aβ. The fact that all the cytokines which increase Aβ production are
proinflammatory cytokines is striking. Taken together, it appears that a vicious circle
accelerates the development of AD, because Aβ peptide activates microglia and
astrocytes which can produce and secrete proinflammatory cytokines. These
proinflammatory cytokines in turn upregulate Aβ generation, which serves to drive a
feedforward mechanism.
Overall, there is overwhelming evidence that the immune system plays an
important role in AD pathology. However, it is complicated to define the immune
system as either neuroprotective or neurotoxic, since the immune response can be
both beneficial and harmful. It remains to be elucidated which circumstances lead to a
neuroprotective or neurotoxic end result.
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The role of inflammation in Alzheimer’s disease
Proinflammatory versus anti-inflammatory cytokines
It appears that a proinflammatory immune response is associated with a
neurotoxic effect. As described above, both increased ROS and Aβ production are
closely
linked
to
proinflammatory
cytokines.
Another
disadvantage
of
proinflammatory cytokines is the inhibition of microglial clearance, because
proinflammatory cytokines restrain Aβ degradation while anti-inflammatory
cytokines promote Aβ degradation (Lee and landreth, 2010). This phenomenon also
contributes to the vicious circle of Aβ accumulation (Figure 4). However, Maier et al.
(2008) have demonstrated both an increase in Aβ deposits as well as a more antiinflammatory M2 phenotype of microglia cells in C3 deficient APP mice. This
implies that the anti-inflammatory phenotype is also not neuroprotective. On the
contrary, they argue that the phagocytosis capacity of microglia is reduced because C3
is necessary for interaction between anti-inflammatory cytokines and the Aβ
degradation capacity of microglia. Remarkably, this study indicates that a reduction in
proinflammatory cytokines can not outweigh the lack of anti-inflammatory cytokines.
In other words, this study suggests that the presence of anti-inflammatory cytokines,
which stimulate phagocytosis in microglia is more important than the absence of
proinflammatory cytokines, which produce toxic end products.
There is indeed evidence that the proinflammatory immune response is present
in the AD brain. For instance, distribution of IL-1α-immunoreactive microglia in the
human brain parallels the eventual distribution of neuritic plaques (Sheng et al., 1998
in combs 2009). Thus, the microglia close to plaques have a proinflammatory
phenotype. Furthermore, a medicine called glatiramer acetate stimulates microglia and
macrophages to have an anti-inflammatory phenotype. This medicine has induced
neuroprotection in animal models of AD (Yong, 2010). Interestingly, the
proinflammatory environment seems only a characteristic in AD and not in healthy
individuals (Cacabelos et al., 1994).
Taken together, it is important that there is balance between proinflammatory
and anti-inflammatory cytokines. It appears that reductions in anti-inflammatory
cytokines decrease the clearance capacity of the immune system and that an increase
in pro-inflammatory cytokines results in more toxic species and production of Aβ. It
is not yet completely understood what causes the increased proinflammatory
inflammation response in AD. Could it be that chronic inflammation changes the
15
The role of inflammation in Alzheimer’s disease
immune response to a more proinflammatory phenotype? Or is normal aging
responsible for changes in the inflammation response?
Figure 4. The proinflammatory vicious circle.
Aβ accumulation activates the immune system. The overall inflammation response can be pro or antiinflammatory. Anti-inflammatory cytokines stimulate degradation of Aβ resulting in a reduction of Aβ.
In AD patients it is seems to be that the inflammation response is proinflammatory. This leads to
increase production of ROS and NO and Aβ. The production of ROS and NO will result in decreased
activity of Aβ degrading enzymes and after a while in neuronal damage. Both the increased production
of Aβ and decreased activity of Aβ degrading enzymes increase the accumulation of Aβ.
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The role of inflammation in Alzheimer’s disease
Aging
Aging of the immune system
The biggest risk factor for AD is age. The definition of aging is interesting
since aging is not defined as reaching a historical age, but as the accumulation of
unrepaired, deleterious changes occurring in molecules, cells, tissue and organs
(Ostan et al., 2008). Lucin et al. (2009) even compare aging with a disease; almost all
factors involved in the immune system increase while genes related to synaptic
function, growth factors and trophic support decrease. The immune system is also
subject of the aging process. In fact, the adaptive immune system seems to decline in
elderly. For example, naïve T-cells decrease radically with age (Fagnoni et al., 2000).
This could explain why the primary and secondary antibody response is weaker and
shorter in old compared to young animals (Goidl et al., 1976). Furthermore, antigenspecific major histocompatibility complex (MHC) class I restricted cytotoxicity is
decreased in the elderly and bone-marrow-derived macrophages present only low
levels of MHC class II due to impaired transcription (Grubeck-Loebenstein and Wick,
2002). Overall, this suggests that the adaptive immune system is diminished in aged
individuals.
On the other hand, the innate immune system seems to be overactive to
compensate for the adaptive immune system. Normal aging results in increased
complement factors, microglia activity and astrocytic activity (Mrak and Griffin, 2005;
Lucin and Wyss-Coray, 2009). For instance, astrogliosis and reactive astrocytes are
common features of aging (Ricci et al., 2009). Interestingly, a lot of the
proinflammatory cytokines are also elevated in older individuals like IL1α, IL1β,
TNFα, IL-6 and IFNγ while some anti-inflammatory cytokines are decreased like IL4,
IL5 and IL10 (Grubeck-Loebenstein and Wick, 2002). This implies that the
inflammation response has a more proinflammatory character in elderly compared to
younger individuals.
The exact cause of both the increased innate immune response and the
proinflammatory nature of this response upon aging, has not been clarified yet. It
could be as mentioned above that increased activity of the immune system tries to
compensate the decline of the adaptive immune system. It is also possible that
reduced inhibition signals of neurons elevate microglial activity (Biber et al. 2007). In
fact, CD200 and fractalkine, which keep microglia in a quiescent state, are reduced in
17
The role of inflammation in Alzheimer’s disease
the aged brain (Lyons et al. 2009). Another explanation could be that with aging
increased expression of toll-like receptors, which recognize pathogen and dangerassociated molecular patterns, generate a hypersensitive state of the innate immune
response (Lucin and Wyss-Coray, 2009). In addition, the observed increase of
infectious diseases in elderly could also explain the enhanced activation of the
inflammation response (Gravenstein et al., 1998).
Aging of the clearance pathways of Aβ
The aging process also seems to have an effect on the different Aβ clearance
pathways. First of all, the overall Aβ degrading enzymes are decreased with aging
(Caccamo et al., 2005). Both aged microglia and astrocytes produce less degrading
enzymes. As mentioned earlier, degrading enzymes can also be substrate of oxidative
damage. For that reason, the increased oxidative stress in elderly can result in reduced
degrading enzymes (Wang, Dickson and Malter, 2006).
Additionally, microglia cells in aged individuals seem to be less able to
remove Aβ. Not only the proinflammatory phenotype is reducing the phagocytosis
capacity, but the microglia morphology also seems to be changed. For instance,
microglia from old mice have fewer processes and are less motile as microglia from
younger mice (Koenigsknecht-Talboo et al., 2008). Streit, Sammons, Kuhns and
Sparks (2004) also describe dystrophic microglia in the aging human brain and
conclude that the microglia in the aged brain undergo senescence. However, it must
be noted that, in this study, only one young and one old case have been used.
Furthermore, aging microglia have reduced Aβ binding receptors (Hickman, Allison
and El Khoury, 2008). Taken together, these results indicate that the ability of
microglia to clear Aβ decreases with age.
Furthermore, old astrocytes do not release MCP-1 in the same way as young
control cells do after stimulation with Aβ. The chemokine MCP-1 is important for
astrocytosis. So this indicates that aging astrocytes are less capable to remove Aβ
(Wyss-Coray et al., 2003). Moreover, late passage astrocytes had also significant
increased expression of senescence markers, but they were still able to produce Aβ
peptides. Interestingly, it seems to be that senescence can be associated with a proinflammatory status of glial cells (Blasko et al., 2004).
To conclude, it seems that age negatively affects the clearance pathways of Aβ.
18
The role of inflammation in Alzheimer’s disease
The transition from normal aging to AD
The question remains when the transition occurs from normal aging to developing AD.
The prevalence of AD roughly doubles every 5 years above 65 years and affects more
than 40% after the age of 85 (Figure 5) (Brayne et al., 2006). The fact that the aging
immune system becomes proinflammatory and undergoes senescence suggests that
every individual will develop AD sooner or later. The finding that the majority of
healthy elderly has diffuse Aβ deposits and tangles supports this idea. However, senile
plaques are only detected in AD patients and NEP and IDE mRNA and protein levels
are significant lower in AD than in age-matched normal control brains (Hoozemans,
veerhuis, rozemuller and Eikelenboom, 2005; Yasojima, McGeer and McGeer, 2001).
Overall, this indicates that the clearance of Aβ decreases with age, due to changes in
the immune system, but that this decline of Aβ clearance is even more severe in AD
patients. The increased aging of the immune system in AD patients resulting in a more
proinflammatory status could be due to certain genetic predispositions.
There is some genetic evidence for this statement. First of all, polymorphisms
in a number of proinflammatory genes such as IL-1, IL-6 and TNFα in AD patients
have strengthened the hypothesis that people with a proinflammatory status have a
predisposition to develop AD (Sastre et al., 2003). Furthermore, in healthy
centenarians genetic markers related to a proinflammatory status are underrepresented
and genetic variants associated with anti-inflammatory activity are highly present.
(Vasto et al., 2007). Finally, in offspring with a parental history of AD the capacity to
produce pro-inflammatory cytokines is higher than in offspring without a history of
LOAD (Exel et al., 2009). Taken together, AD patients have genetically a more
proinflammatory immune system. This proinflammatory status is evolutionary
beneficial
to
survive
infection
diseases
in
childhood,
but
becomes
too
proinflammatory with age resulting in a negative vicious circle of Aβ accumulation.
The phenomena that AD has an early onset in which the production of Aβ is
altered and an late onset in which an age-related proinflammatory inflammation
response decreases the removal of Aβ, can also be observed in other diseases.
Diabetes and arteriosclerosis have both early and late onset variants. The late onset
variants are associated with a proinflammatory inflammation response. For example,
insulin resistance is caused by proinflammatory cytokines inhibiting insulin receptor
signalling pathways (Libby, 2002; Shoelson, Lee and Goldfine, 2006). This
19
The role of inflammation in Alzheimer’s disease
demonstrates that an age-related low-grade chronic upregulation of proinflammatory
response has crucial consequences for elderly.
Prevalence of AD
45
40
35
30
%
25
20
15
10
5
0
65
70
75
80
85
Age
Figure 5: Prevalence of AD by population age.
Dementia rates doubles every five years after the age of 65. The prevalence of AD is more than 40%
after the age of 85.
20
The role of inflammation in Alzheimer’s disease
Conclusion
In summery, AD is characterized by Aβ deposits. These Aβ accumulations are
both in EOAD and LOAD the result of the imbalance between Aβ production and Aβ
clearance. The clearance of Aβ is a multi-factorial process which includes the
inflammation response. The inflammation response is an important and early event in
AD pathology, but it is complicated to define the immune system as either
neuroprotective or neurotoxic. It appears that a proinflammatory immune response has
a neurotoxic effect whereas an anti-inflammatory response is associated with a
beneficial effect, because proinflammatory cytokines lead to production of Aβ and
toxic species whereas anti-inflammatory cytokines stimulates Aβ clearance. Both a
defect in the Aβ clearance pathways as a proinflammatory status have been observed
in LOAD patients. Interestingly, the biggest risk factor for AD is aging, which
changes the immune response to a more proinflammatory character and also decreases
the efficiency of Aβ clearance. Genetic evidence suggests that in individuals who
develop LOAD, the immune response becomes too proinflammatory with aging,
resulting in a negative vicious circle of Aβ accumulation (Figure 6).
It must be noted that many proteins, factors and processes are involved in the
imbalance of Aβ production and clearance, in the inflammation response and in the
aging process and all these factors influence and interact with each other. Therefore,
many different factors can be responsible and involved in the development of LOAD.
Future studies are necessary to expose all the interactions within and between
clearance, inflammation and aging. It would also be interesting to investigate how
other risk factors for the development of AD influence the removal of Aβ,
inflammation response and aging process. A good example of a risk factor which
influences the different processes is diabetes mellitus (Breteler, 2000). Normally,
insulin suppresses several proinflammatory transcription factors. An impairment of
insulin activity results in the activation of these proinflammatory factors. The
increased proinflammatory state during insulin resistance could explain why diabetes
mellitus is involved in the development of AD (Ostan et al. 2008).
21
The role of inflammation in Alzheimer’s disease
Figure 6: The influence of aging on the vicious circle of Aβ accumulation.
Aging influence the imbalance between Aβ production and clearance, because the clearance of Aβ
decreases with age. Furthermore, aging stimulates a proinflammatory status, which results in even a
bigger
imbalance
of
Aβ
production
and
22
clearance
and
increased
Aβ
production.
The role of inflammation in Alzheimer’s disease
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