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The role of inflammation in Alzheimer’s disease The role of inflammation in Alzheimer’s Disease 0044 O Occttoobbeerr 22001100 JJuuddiitthh vvaann ddeerr H Haarrgg ((00440055555588)) U Unniivveerrssiittyy ooff A Am msstteerrddaam m B Brraaiinn & &C Cooggnniittiivvee SScciieenncceess N Neeuurroosscciieennccee SSuuppeerrvviissoorr:: PPiieett E Eiikkeelleennbboooom m C Coo--aasssseessssoorr:: PPaauull L Luuccaasssseenn 1 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 2 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. 3 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). 4 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 5 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. 6 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. 7 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. 8 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 9 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). 10 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, 11 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). 12 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) 13 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. 14 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. 16 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. 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