Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease

Advanced Drug Delivery Reviews 54 (2002) 1627–1656 www.elsevier.com / locate / drugdeliv

Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease Amy H. Moore, M.K. O’Banion* Departments of Neurobiology and Anatomy and Neurology, School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Avenue, Box 603, Rochester, NY 14642, USA

Abstract Neuroinflammation is now recognized as a prominent feature in Alzheimer’s pathology and a potential target for therapy aimed at treatment and prevention of disease. This review provides a synopsis of current information about cellular and molecular mediators involved in Alzheimer’s neuroinflammation as well as interactions between these mediators that influence pathology. Anti-inflammatory therapies, particularly nonsteroidal anti-inflammatory drugs, are considered from experimental and clinical perspectives and potential mechanisms underlying their apparent benefits are discussed. Finally, possible protective effects of the inflammatory response in Alzheimer’s are described. Taken all together, evidence presented in this review suggests a scheme for Alzheimer’s pathogenesis, with neuroinflammation playing a crucial role influencing and linking b-amyloid deposition to neuronal damage and clinical disease.  2002 Elsevier Science B.V. All rights reserved. Keywords: Ab; Anti-oxidants; Astrocytes; Cyclooxygenase; Cytokines; Microglia; Nonsteroidal anti-inflammatory drugs

Contents 1. Introduction ............................................................................................................................................................................ 2. Neuroinflammation as a hallmark of Alzheimer’s disease pathology............................................................................................ 2.1. Glial cell activation .......................................................................................................................................................... 2.1.1. Microglia and astrocytes ......................................................................................................................................... 2.1.2. Aging enhances glial responsiveness........................................................................................................................ 2.1.3. Ab as a primary inflammatory stimulus ................................................................................................................... 2.1.4. Inflammation may link Ab deposition to neurofibrillary changes ............................................................................... 2.1.5. Neurodegeneration enhances glial activation ............................................................................................................ 2.1.6. Role of cerebrovasculature in AD neuroinflammation ............................................................................................... 2.2. Components of the neuroinflammatory cascade .................................................................................................................. 2.2.1. Proinflammatory cytokines...................................................................................................................................... 2.2.2. Chemokines ........................................................................................................................................................... 2.2.3. Prostaglandins, nitric oxide and reactive oxygen species ........................................................................................... 2.2.4. Complement ..........................................................................................................................................................

*Corresponding author. Tel.: 1 1-585-275-5185; fax: 1 1-585-756-5334. E-mail address: kerry [email protected] (M.K. O’Banion). ] 0169-409X / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0169-409X( 02 )00162-X

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2.3. Gene polymorphisms and neuroinflammation in AD ........................................................................................................... 3. Anti-inflammatory therapies in AD ........................................................................................................................................... 3.1. Epidemiology of anti-inflammatory therapies in AD ........................................................................................................... 3.2. Nonsteroidal anti-inflammatory drugs and AD.................................................................................................................... 3.2.1. Evidence from animal models ................................................................................................................................. 3.2.2. Cyclooxygenases in AD.......................................................................................................................................... 3.2.3. Other potential actions of NSAIDs .......................................................................................................................... 3.2.4. Other targets in the prostaglandin pathway ............................................................................................................... 3.3. Anti-inflammatory actions of other drugs ........................................................................................................................... 3.3.1. Estrogen ................................................................................................................................................................ 3.3.2. Vitamin E and other anti-oxidants ........................................................................................................................... 4. Clinical trials of anti-inflammatory drugs in Alzheimer’s disease ................................................................................................ 4.1. Nonsteroidal anti-inflammatory drugs ................................................................................................................................ 4.2. Other anti-inflammatory drugs .......................................................................................................................................... 5. The potential protective role of inflammation in Alzheimer’s disease .......................................................................................... 6. Summary ................................................................................................................................................................................ Acknowledgements ...................................................................................................................................................................... References ..................................................................................................................................................................................

1. Introduction Starting with neuropathological recognition of a few inflammation-related changes and evidence that arthritis sufferers were less likely to have disease, a decade of intense research has placed neuroinflammation alongside tangles and neuritic plaques as a hallmark feature of Alzheimer’s disease (AD). Best considered a local tissue response with little or no involvement of the peripheral immune system, neuroinflammation in AD is a complex process, with multiple mediators, signaling pathways, and feedback loops. In conjunction with epidemiological and genetic evidence, information about these mediators and their interactions has increased the number of potential specific targets for intervention. Yet the extent to which neuroinflammation contributes to disease pathogenesis is still not fully understood. Although many of these topics have been recently reviewed, this article will provide a broad and current overview of the cellular and molecular elements contributing to neuroinflammation, and data supporting its integral role in AD. Evidence for the use of anti-inflammatory therapies in AD will then be considered, with particularly emphasis on targets of nonsteroidal anti-inflammatory drugs (NSAIDs), the principle drugs implicated in epidemiological studies for prevention of AD. Current clinical studies utilizing NSAIDs and other anti-inflammatory strategies will also be addressed. Finally, consideration

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will be given to possible negative outcomes of antiinflammatory strategies in Alzheimer disease.

2. Neuroinflammation as a hallmark of Alzheimer’s disease pathology Although markers of neuroinflammation are prominent in numerous CNS conditions including traumatic brain injury [1,2], stroke [3–5], Parkinson’s disease [6], and multiple sclerosis [7–9], its presence as a cause or a consequence of the pathology has yet to be discerned. However, ongoing research provides increasing evidence that inflammation plays an intimate and integral role in the development of Alzheimer’s disease. The association of cellular elements and inflammatory mediators with AD represents one major focus of research. The extent and details of findings in this area have been reviewed by others and are too numerous to address in this article [10]. However, recent investigations and developments reinforce several hypotheses and warrant discussion.

2.1. Glial cell activation Inflammation is a common player in the brain’s response to injury and pathology. Although the ultimate consequence of these situations is the compromise and / or loss of functional neurons, there

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is growing research highlighting and focusing on the integral roles of reactive astrocytes and microglia in the initiation and exacerbation of CNS inflammation. The functions of these cells in the normal and pathological CNS have been thoroughly reviewed [11–14] and will only be briefly described. Astrocytes, the most abundant cells in the CNS, serve multiple functions such as contributing to the structure and preservation of the blood–brain barrier (BBB), buffering and maintaining homeostasis of the extracellular environment, and generating energy substrates in conditions of functional demand. Microglia, the resident macrophages of the CNS, maintain a low profile in basal conditions, existing as watch dogs and scavengers by identifying and engulfing cellular debris. However, in the presence of an inflammatory stimulus, astrocytes and microglia demonstrate a reactive phenotype that is characterized by a more spherical cell soma, hypertrophy of nuclei, elongation / extension of processes and expression / release of a large number of proteins. These secreted products include cytokines, growth factors and reactive oxygen species—all inflammatory mediators that launch numerous signaling pathways. It is the interaction of these glial cells and their products that largely determine the profile and sequence of inflammatory events. Initially arising as a necessary and beneficial response for neural repair and maintenance, chronic periods of glial activation may be deleterious to surrounding nervous tissue. From a therapeutic standpoint it is therefore imperative to identify and understand the role of inflammation in neurodegeneration.

2.1.1. Microglia and astrocytes Classic neuropathological lesions of Alzheimer’s disease are senile plaques composed of b-amyloid (Ab) and neurofibrillary tangles (NFT) harboring hyperphosphorylated t protein. Numerous studies have demonstrated an intimate association between activated microglia and senile plaques (reviewed in Ref. [15]). Similar to peripheral macrophages, these microglia express major histocompatibility complex type II (MHCII), pro-inflammatory cytokines, chemokines, reactive oxygen species, and complement proteins. Interestingly, microglia isolated from AD brain showed higher colony-stimulating factor and C1q production than microglia isolated from

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nondemented brain [16]. In addition to human postmortem studies, transgenic animal models of AD also develop plaque pathology in association with glial activation [17,18]. Several investigators have proposed neuroprotective qualities of astrocytes and microglia [17–20]; however, the majority of in vitro and in vivo research remains focused on the destructive nature of glial activation. The presence of activated microglia in the vicinity of neuritic plaques may simply be a non-specific inflammatory response. However, this glial population appears to favor amyloid-containing plaques, indicating a specific interaction between Ab and microglia. As will be discussed in Section 2.1.3, microglia may be activated by Ab, leading to initiation of inflammation. In addition, microglia may mediate plaque formation in the AD brain. For example, evidence suggests that microglia assist in the conversion of non-fibrillar Ab to fibrillar Ab, and consequently, the development of neuritic plaques from diffuse plaques [21–24]. Moreover, numerous researchers have described the ability of microglia to phagocytose and internally degrade Ab deposits [25,26], a process that may be important for plaque evolution. The association between activated microglia and senile plaques may also contribute to neuritic dysfunction through glutamate release and resultant focal excitotoxicity to synaptic regions [27]. Similar to microglia in AD brain, reactive astrocytes are found in the vicinity of neuritic plaques and show increased expression of inflammation-related proteins. However, their disposition around the neuritic halo suggests a role separate from that of the microglia. Recent studies in vitro have suggested that astrocytes create a barrier around the plaque through deposition of proteoglycans, preventing phagocytosis by microglia [26,28]. Evaluation of post-mortem AD brain indicates localization of proteoglycans to the neuritic plaques [29], reinforcing the impeding characteristic of astrocytes in AD.

2.1.2. Aging enhances glial responsiveness It is well known that the single most important risk factor for AD is age. One reason for this association is that the progression from initial pathophysiological event to clinical detection is likely to be on the order of decades. This is most clearly illustrated by pathological studies showing an

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age-associated increase in the distribution of NFT and Ab deposits, with some individuals harboring pathology as early as in the second decade of life [30]. Similar age-associated pathological changes have been demonstrated in the brains of Down’s syndrome patients [31–33]. Other cited reasons have included accumulation of oxidative damage, mitochondrial mutations, loss of plasticity, and vascular changes with age. Interestingly, the brain also appears to have an enhanced inflammatory response with aging. For example, astrocyte activation, as evidenced by glial fibrillary acidic protein (GFAP) expression, increases with age in rodents as well as people [34], and the number and distribution of activated macrophage / microglial cells is increased in rat brain with age [35]. Furthermore, the glial response to injury is enhanced in aged brain [36,37] and is accompanied by marked changes in the inducibility of many inflammation-associated genes [38]. Evidence that the glial response to Ab infusion is greater in aged than in young primates [39] further reinforces the notion that an increased local brain inflammatory response may underlie at least part of why AD is an age-associated disease.

convincingly demonstrated that Ab and APP activate glia in a dose- and time-dependent manner [46–48], as measured by morphological response and expression of the potent pro-inflammatory cytokines interleukin-1b (IL-1b) and tumor necrosis factor-a (TNFa). Moreover, the release of proteins from activated glia enhances Ab-induced glial activation [48], creating a continuous cycle of inflammatory stimuli. The mechanism by which Ab stimulates glia is still unclear; however, there is evidence that the peptide induces activation of nuclear-factor kB (NFkB) [46,49], a transcription factor implicated in the induction of numerous genes, including cytokines, acute phase proteins and immunoreceptors. Using primary rodent glial cell cultures, Ab-induced increase in IL-1b and IL-6 mRNAs was inhibited by pretreatment with anti-sense NF-kB oligonucleotides [49]. Activation of NF-kB may be through Ab’s chemokine-like activity at formyl chemotactic receptors [50] or through Ab’s binding to the receptor for advanced glycation endproducts (RAGE) [51– 54]. Antagonists to both of these receptors have prevented Ab-stimulated IL-1b release [50,51].

2.1.3. Ab as a primary inflammatory stimulus Activation of glial cells initiates a sequence of molecular and cellular events that can self-propagate the neuroinflammatory process. Therefore, determining the trigger of activation is key to understanding the contribution of inflammation in AD and other neurodegenerative diseases. A strong candidate for the triggering stimulus in Alzheimer’s disease is Ab. A peptide derived from the amyloid precursor protein (APP), Ab is a principal component of senile plaques. Ab is normally produced in brain but cleared before accumulating in the extracellular space. However, based on genetic, pathological, and transgenic evidence, deposition of Ab is considered a crucial step in the onset of AD (reviewed in Ref. [40]). Neurotoxicity may represent one role for Ab in AD neuropathogenesis since Ab (and APP) has been shown to induce neuronal apoptosis in vitro [41,42] and in vivo [43,44]. In addition to direct neurotoxic effects, investigators have hypothesized that Ab is a factor in glial activation, given that reactive glial cells are spatially intimate with Ab deposits [45]. In vitro studies have

2.1.4. Inflammation may link Ab deposition to neurofibrillary changes An ongoing debate in Alzheimer’s research relates to the etiology and connection between amyloid plaques and neurofibrillary tangles, as well as their relative contribution to disease. Although a number of studies have linked neurofibrillary tangle numbers to synaptic loss and cognitive decline [55,56], genetic evidence strongly supports dysregulation in APP processing as causative for familial AD [40]. Moreover, Ab deposition and levels of Ab peptides are also correlated with cognitive decline [57,58]. Interestingly, an analysis of frontal cortex in 62 brains from patients with different degrees of dementia suggested that increases in Ab peptide levels preceded formation of NFT and that both lesions occurred before clinical criteria for AD were met [57]. A connection between Ab and NFT formation has also been established in transgenic mice. In two separate studies, NFT numbers in t mutant animals were increased by intracerebral injection of aggregated Ab and by cross-breeding with mutant APP transgenic mice [59,60]. However, the absence of

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Ab deposits in frontotemporal dementia with parkinsonism, where large numbers of NFT accumulate due to a mutation in the t protein on chromosome 17 [61,62], has been cited as demonstrating that plaques do not arise from NFT [63]. Despite these observations, the mechanism(s) underlying the connection between plaques and tangles is not yet known. One intriguing possibility is that the local inflammation response to Ab may trigger NFT generation. Cases of high-plaque density brains in non-demented individuals showing little or no inflammatory changes have been cited to support the requirement of inflammation for AD [64]. Interestingly, the regional distribution of microglia parallels that of tangle distribution [65] and activated microglia have been correlated with the presence of NFT [66]. Moreover, proinflammatory cytokines such as IL-1b, a major product of activated microglia in AD, modulate neuronal kinase activities and lead to changes in t phosphorylation and conformation reminiscent of NFT [67]. With the availability of the transgenic models alluded to above, the hypothesis that inflammatory changes play a role linking Ab to NFT can now be addressed.

2.1.5. Neurodegeneration enhances glial activation In addition to stimulating inflammatory pathways, the classical plaques and tangles that characterize AD are believed to contribute to neuronal dysfunctional and eventual death. As demonstrated in numerous CNS disorders, inflammatory mediators are often associated with regions of cell loss. Therefore, it has been proposed that factors released from damaged and dying neurons initiate an inflammatory response, setting in motion a self-sustaining wave of neurodegeneration [68]. One study has demonstrated that excitotoxic neuronal damage, induced by injection of quisqualic acid, leads to local and diffuse microglial and astrocytic activation in vivo [69]. This reactive gliosis is characterized by morphological changes, release of pro-inflammatory cytokines, increase in inducible nitric oxide synthase (iNOS) expression and elevated production of prostaglandins. In another study aimed at understanding the effect of compromised neurons on glial activation [70], TNFa, used as an index of glial activation, was found significantly elevated in mixed glial monolayers exposed to homogenates from hippocampal

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neurons damaged by either sonification or by trimethyltin chloride (TMT) treatment. Interestingly, the elevation in TNFa was also observed in glial monolayers incubated with CSF from Alzheimer’s disease patients, suggesting that factors released during states of neurodegeneration elicit glial activation in vivo. This glial activation was determined to be partially dependent on the activity of caspases, a class of cysteine proteases that are involved with apoptotic cell death, including neurons. Specifically relevant to AD, neuronal apoptosis was shown to result in Ab accumulation through a caspase-3 mediated mechanism [71]. Since Ab can induce apoptosis in neighboring neurons [41,43,44], a selfpropagating and damaging cycle may be established. Based on these findings, one could postulate that neurodegenerative processes in AD exacerbate the inflammatory response and ultimate tissue damage, through direct enhancement of glial activation and augmentation of Ab production.

2.1.6. Role of cerebrovasculature in AD neuroinflammation One pervasive question when considering neuroinflammation is how circulating inflammatory mediators affect the CNS. In the past decade, mounting effort has been devoted to understanding how the cerebrovasculature participates in the inflammatory response. Microvascular pathology is common in AD and characterized by reduced cerebral blood flow, malformation of cerebral microvessels, thickening of the basement membrane, atherosclerosis, amyloidosis [72], and endothelial cell degeneration [73]. In vitro, Ab inhibits nitric oxide (NO) production by cultured endothelial cells and compromises vessel sensitivity to endothelium-dependent vasodilation [74]. However, unlike some neurodegenerative disorders, neuroinflammation in AD occurs in the absence of invading leukocytes, indicating that the alterations in vessels are not soliciting a systemic inflammatory response. Instead, vascular cells themselves may be a focus of AD inflammation, contributing to the overall inflammatory response. Namely, Ab can induce endothelial cell degeneration [75–77], potentially initiating glial activation (as described in Section 2.1.5) and neuronal death [78]. The compromised function of vasculature in AD is important when considering the hypothesized transport of Ab across

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the BBB [79]. Increased Ab deposition in the AD brain may be a consequence of IL-1 induction of APP mRNA [80] and protease [81] in the endothelial cells and / or altered cerebrovasculature transport of Ab across the BBB [82,83].

2.2. Components of the neuroinflammatory cascade Glial activation results in the release of a spectrum of inflammatory mediators, initiating multiple signaling pathways that are independent yet related and influenced by each other. The roles of each inflammation-related protein are too extensive to address in this article and have been described in other reports [10] but the relationships among certain players deserve discussion. Ultimately, it is this interaction of pro- and anti-inflammatory molecules that determines the magnitude and duration of the inflammatory response.

2.2.1. Proinflammatory cytokines As described earlier, reactive glia produce a variety of molecules that trigger and contribute to chronic inflammation. Termed ‘the cytokine cycle’ [84], pro-inflammatory cytokines participate in a spectrum of signaling events that continuously feedback and influence each other. Microglial-derived IL-1b appears to be a driving force in this process. IL-1b has been previously shown to be a potent immunomodulating cytokine that induces multiple inflammatory mediators in astrocytes and neurons [13]. IL-1b overexpression is a consistent feature of post-mortem AD brain, with double-labeling immunohistochemical studies localizing IL-1b to plaque-associated microglia [85–87]. In addition to initiating and sustaining inflammation-related events and modulating neurons [13,85], IL-1b appears to be directly involved in AD pathophysiological alterations. Its regional expression around plaques and temporal profile of immunoreactivity relative to pathology implicates IL-1b as a mediator of plaque and tangle formation. This idea is supported by results describing IL-1b-influenced synthesis and processing of APP [88–90], leading to greater Ab production and disposition. As alluded to in Section 2.1.4, evidence for IL-1b involvement in tangle formation comes from studies using implanted pellets that slowly release IL-1b to mimic a state of

chronic inflammation [67]. In these studies, release of IL-1b was associated with phosphorylation of neurofilaments and increased t immunoreactivity in the rat hippocampus. In addition to mediation of plaque and tangle evolution, IL-1b may also take part in the cholinergic dysfunction found in AD. Acetylcholinesterase (AChE), an enzyme that breaks down acetylcholine, is up-regulated in regions of AD brain. This up-regulation is believed to minimize the availability of acetylcholine at the synapse, thereby contributing to cognitive decline. Interestingly, neuronal AChE expression and activity were increased ¨ PC-12 cells co-incubated with microglial in naıve cells that had been stimulated with APP-rich media [91]. The role of IL-1b in this cascade was demonstrated in vivo with the observation that chronic release of IL-1b (as described above) into rat cortex increased AChE mRNA levels. Taken together, these results indicate a powerful role of IL-1b in the inflammation, pathology and neuronal dysfunction associated with AD. The availability of specific reagents that block IL-1b signaling, such as IL-1 receptor antagonist and IL-1 receptor deficient mice, should allow a more thorough understanding of IL1b’s role in AD pathogenesis. Other molecules have significant roles in ADrelated inflammation. TNFa, a pro-inflammatory cytokine secreted primarily by activated macrophages and microglia, is known to promote cell survival and death in the CNS [92]. Immunohistochemical studies show an increase in microglial TNFa localized to senile plaques, suggesting its participation in Ab-induced inflammation [93]. Recent research has demonstrated that TNFa is essential for Ab-induced neurotoxicity [94,95]; however, the mechanism by which this occurs, and whether it is inflammation-independent has yet to be elucidated. Transforming growth factor-1 (TGF-b1) is another multifunctional cytokine that appears to be involved in the progression of AD pathology. Associated with the response to brain injury [96], TGF-b1 is found upregulated in stroke [97] and neurodegenerative conditions [98]. Likewise, elevated levels of TGF-b1 have been detected in plaques [99], serum [100] and cerebral spinal fluid [101] of AD patients. Predominantly localized to glial cells, TGFb1 participates in glial scarring by inducing a variety of factors associated with Ab plaques, including

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extracellular matrix proteins [10]. This relationship suggests that TGF-b1 is a modulator of Ab deposition. Indeed, studies of double transgenic mice expressing human APP and TGF-b1 show that animals constitutively expressing TGF-b1 develop perivascular astrocytosis and amyloid deposition in cerebral blood vessels [102]. Moreover, TGF-b1 overexpression also leads to endothelial cell damage and degeneration [103], a common pathology observed in AD. In contrast to marked effects on Ab deposition in cerebrovasculature, these same transgenic animals exhibit diffuse microglial activation and decreased extent of parenchymal Ab deposition and neuritic dystrophy [104]. These findings suggest that TGF-b1 may upregulate microglial clearance of Ab and underscore cell type-specific actions of this multifunctional cytokine.

2.2.2. Chemokines Chemokines are a family of structurally and functionally related small proteins that participate in inflammatory-cell recruitment and include IL-8, MIP-1, -2 (macrophage inflammatory proteins), MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, normal T-cells, expressed and secreted). The chemokines are divided into four families (CXC, CC, C, CX 3 C) and the specific structure and receptors (CXCR1-4, CCR1-8, CX 3 CR1) of each domain are described elsewhere [105,106]. Chemokines are predominantly expressed by astrocytes, microglia, and endothelial cells and act on receptors located on neurons, microglia, and circulating leukocytes [106]. Under normal conditions, chemokines and their receptors are detected at low levels. However, similar to other inflammatory mediators, chemokine expression is elevated in neurodegenerative conditions such as traumatic brain injury, stroke, multiple sclerosis, and HIV dementia. In Alzheimer brain, the regional profile of chemokines and their receptors have been described [107]. Receptors show region / cell-specific upregulation with increased CXCR2 occurring within some senile plaques and increased expression of CCR3 and CCR5 on reactive plaque-associated microglia. Interestingly, elevations in MCP-1 [108] and MIP-1b [109] immunoreactivity in glia cells are also localized to plaque pathology. The observation that Ab can stimulate production of chemokines in primary

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microglia and human monocytes [16,108,110–112] identifies a potential role between amyloid-containing plaques and chemokines. Experimental findings suggest that chemokines play a role in leukocyte recruitment into the CNS, demonstrated by increased number of monocytes following intra-hippocampal injections of chemokines and diffuse neutrophil and monocyte infiltration in transgenic mice overexpressing selected chemokines [106]. Although this role is applicable to other neurodegenerative disorders, AD is not characterized by the migration of leukocytes across the BBB. Therefore, chemokines are likely to subserve another function in AD. Based on their locale in the AD brain, chemokines and their receptors may be responsible for recruiting glial cells to the senile plaques. Whether this recruitment results in beneficial or detrimental consequences has yet to be determined.

2.2.3. Prostaglandins, nitric oxide and reactive oxygen species The release of IL-1b, TNFa and other pro-inflammatory cytokines sets into motion numerous signaling pathways and events. One such pathway is the conversion of arachidonic acid into prostaglandins via cyclooxygenase (COX). Because cyclooxygenase is the principle target of nonsteroidal antiinflammatory drugs (NSAIDs), consideration of this important pathway will be largely reserved for Section 3. For the current discussion it is worth noting that prostaglandins in the brain are involved in regulation of body temperature, vasoactivity, sleep, and inflammation (reviewed in Refs. [113,114]). Among these small lipid molecules, prostaglandin E 2 (PGE 2 ) is a pro-inflammatory mediator and the predominant product of COX pathways during inflammation [115]. Treatment of cultured astrocytes with IL-1b led to increased PGE 2 production [116] and Ab stimulated COX pathways in cultured microglia [93,117]. Importantly, PGE 2 levels were found to be elevated in CSF from AD patients relative to controls [118,119]. Whether PGE 2 is neurotoxic [120], neuroprotective [121] or neuromodulatory [122] in the AD brain is still under debate. The implications and importance of this research in the treatment of AD will be examined in later sections. Once activated, glia can create more cellular

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damage by contributing to the formation of reactive oxygen species (ROS). The potential creation and roles of such species in AD has been thoroughly reviewed [123–125]. For example, it is widely recognized that activation of microglia by Ab results in elevation of several markers of oxidative stress. Interestingly, Ab increases microglial superoxide anion production without a concomitant rise in NO production in vitro, an imbalance that may lead to oxidative damage [126]. In support of this possibility, changes in the activation of superoxide-forming NADPH oxidase were found in microglia of AD brain [127]. It has been well established that reactive astrocytes produce nitric oxide via cytokine-mediated induction of iNOS, likely contributing to an increase in free radical formation during inflammation in several neurodegenerative states [128]. Reinforcing the interaction and feedback between cell types, Ab stimulates microglial-derived IL-1b, which mediates iNOS expression in reactive astrocytes [46]. In fact, this process is detected in post-mortem AD brain by increased plaque-associated astrocytic iNOS expression [129] and peroxynitrite damage [130]. In addition to direct damage, ROS can dramatically influence cell signaling pathways, particularly those involved in cytokine and other inflammatory modulator production. For example, prostaglandin production is influenced by nitric oxide in both microglia and astrocytes [131,132]. Moreover, in a model of focal ischemia inhibition of nitric oxide synthase blunted PGE 2 production [133]. Although strong evidence implicates AD pathology as the impetus for oxidative stress, recent investigations suggest that oxidative damage is integral to mechanisms of AD progression. This is supported by the finding of increased levels of isoprostanes, markers of lipid peroxidation, in AD transgenic mice prior to amyloid plaque foundation [134]. Interestingly, an alternative hypothesis for the potential neuroprotective effects of NSAIDs is through direct scavenging of peroxynitrite radicals [135].

2.2.4. Complement Although thoroughly reviewed elsewhere [136,137], it should be noted that most proteins from the complement system are up-regulated in Alzheim-

er’s disease. In general, complement activation results in a series of enzymatic reactions that will ultimately recruit inflammatory cells to the site of injury, form the membrane-attack complex, and mark the pathogen / debris for phagocytic clearance. This system may become detrimental if chronically activated or activated in a state of existing inflammation. In agreement with other markers of inflammation, increases in complement proteins are reported in AD brain without a rise in complement inhibitors, suggesting an over-active and non-regulated immune response [138] that would lead to amplification of the inflammatory process. Indeed, there is clear evidence that the full complement cascade is activated in AD since the final membrane-attack complex has been demonstrated on the surface of neuronal processes in AD brain [139]. In addition, numerous investigators have reinforced Ab’s role as a primary trigger of the inflammatory response, by demonstrating association of C1q with b-amyloid plaques in Alzheimer’s disease [140], Down’s syndrome [141], and transgenic animals [142]. Moreover, this first component of the classical complement pathway may directly contribute to Ab fibril formation [143]. Finally, increased levels of C1q may lead to greater Ab accumulation and deposition since C1q was shown to block microglial ingestion of the peptide [144].

2.3. Gene polymorphisms and neuroinflammation in AD a1-Antichymotrypsin (ACT) is an acute phase reactant protein that is upregulated in AD and is believed to play a role in promoting Ab fibrillization [145,146]. In support of this hypothesis, overexpression of a1-ACT increases Ab deposition in double transgenic mice [147]. Interestingly, several studies have reported linkage between AD and a common polymorphism in the signal peptide of the a1-ACT gene [148–150]. However, this linkage has not been demonstrated in other studies and the mechanism by which this polymorphism in a1-ACT influences AD pathogenesis has not been established [151–153]. a2-Macroglobulin (MAC) is an acute phase protein and protease inhibitor that plays an important modulatory role in inflammatory reactions through

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its interactions with the a2-MAC receptor / low density lipoprotein receptor-related protein (reviewed in Ref. [10]). Like many other acute phase proteins, a2-MAC is elevated in AD and associated with Ab plaques [154,155]. Several studies have shown an association between two a2-MAC polymorphisms and AD [156–158], although other studies have failed to reproduce these findings [152,159,160]. Polymorphisms in the IL-1 cluster located on chromosome 2, which includes the genes for IL-1a, IL-1b, and the IL-1 receptor antagonist, have been shown to be associated with an increased risk for rheumatoid arthritis, periodontal inflammation, multiple sclerosis, and myasthenia gravis [161–164]. More recently, three independent studies have revealed increased susceptibility to AD (odds ratio ranging from 3.0 to 7.2) for people homozygous for the IL-1A(-889) allele 2 [165–167]. Interestingly, the IL-1A allele 2 appears to confer susceptibility at an earlier age [166,168] and is associated with an increased rate of cognitive decline [169]. Although it is not yet known whether the IL-1A allele confers increased IL-1a production, an even greater risk for AD was observed in people also homozygous for allele 2 of IL-1B ( 1 3953), a variant previously associated with increased IL-1b secretion in vitro [170]. Together these studies strongly support previous evidence that IL-1 plays a driving force in AD neuroinflammation and pathology [84,171,172]. In addition to evidence that polymorphisms in IL-1 confer greater susceptibility to AD, several polymorphisms in TNFa have also been associated with late-onset AD [173]. In another study, a different polymorphism in the upstream regulatory region of TNFa was associated with an increased risk of vascular dementia as well as an increased risk for AD in those individuals who were also ApoE4 carriers [174]. Interestingly, these same TNF alleles were previously reported to be associated with other inflammatory diseases and may confer increased TNF production [175–177]. However, no association was observed between these alleles and TNF levels in CSF of AD or control subjects, despite the fact that TNFa levels were elevated in the AD population relative to controls [178]. Finally, a genetic variant of IL-6 is associated with a decreased risk for AD [179]. It would be interesting to determine whether this variant leads to decreased cytokine production.

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3. Anti-inflammatory therapies in AD

3.1. Epidemiology of anti-inflammatory therapies in AD More than 20 studies have been published to date addressing the issue of whether anti-inflammatory therapies, particularly the use of NSAIDs, are beneficial for AD. These studies have been reviewed in detail elsewhere [180–183]. Generalized conclusions arising from this body of work include: (1) Initial studies suggesting benefits of anti-inflammatory therapies were based on examining the prevalence of AD in populations with arthritis versus those without [184,185]. Potential confounding effects of genetic predisposition have been largely eliminated by investigations examining discordant rates among twins and siblings in families at increased risk for AD [186,187]. (2) Although some reports suggest that glucocorticoids and related anti-inflammatory therapies may be of benefit [181,186], the majority of studies focus on the use of NSAIDs. This is due in large part to the widespread use of such compounds in the general population. (3) A meta-analysis of 17 reports showed a general consensus of findings, with NSAID therapy being associated with a decreased risk of about 50%. (4) While many earlier studies were of the casecontrolled design, results from the prospective Baltimore Longitudinal Study of Aging have confirmed that NSAID use is beneficial in preventing AD [188]. Important additional outcomes of that study include: (1) the benefit increased with duration of drug use; (2) standard NSAIDs such as ibuprofen showed benefit, aspirin use was associated with a smaller, statistically insignificant effect, and acetaminophen showed no benefit. (5) All epidemiological studies to date rely on data obtained with standard NSAIDs, so no conclusions about the relative benefits of COX-2 selective inhibitors can be made. (6) All of these epidemiological studies depend on an endpoint of clinical diagnosis with AD, so

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should largely be interpreted as showing a role of NSAIDs in preventing or delaying disease onset. As detailed in a later section, data from clinical studies that address the use of NSAIDs in treatment of AD are relatively sparse.

3.2. Nonsteroidal anti-inflammatory drugs and AD Based largely on the epidemiological findings mentioned above and a few clinical reports, there is great interest in the use of NSAIDs for treatment and prevention of AD. These drugs are a mainstay of treatment for many inflammatory conditions and are largely understood to act by inhibiting an ongoing inflammatory reaction as opposed to acting at the root cause of most conditions. The principal target of NSAIDs is the enzyme cyclooxygenase (COX) that catalyzes the first step in the conversion of arachidonic acid to prostanoids, a group of potent lipid mediators acting in diverse physiological processes. Cyclooxygenase is known to exist in two isoforms: COX-1, which in many tissues appears to be constitutively expressed and responsible for homeostatic production of prostanoids; and COX-2, which is often referred to as the ‘inducible’ isoform since its expression is rapidly modulated in response to diverse stimuli such as growth factors, cytokines, and hormones. The distinction between these two isoforms, the roles they play, and the actions of prostanoids have been widely reviewed [113,189– 192]. Key findings relevant for consideration in this review include: (1) COX-2 is the principal enzyme involved in peripheral inflammation and as such has been the focus for development of a new generation of NSAIDs, the coxibs, that preferentially inhibit COX-2 and thus avoid the side effects associated with inhibition of COX-1 such as gastric bleeding [193]; (2) prostaglandin E 2 (PGE 2 ) is the principal product involved in peripheral inflammation [194]; and (3) the roles of COX-1 and -2 in the CNS are complex and not well understood; for example, COX-2 is expressed by neurons under normal conditions and regulated by synaptic activity [114,195,196]. This last point underscores a major problem in interpreting the epidemiological and clinic findings of NSAID benefits in AD. Thus it is not clear whether the benefits of NSAIDs in AD arise from purely anti-inflammatory actions or from

less well-defined neuroprotective roles. Moreover, the enzymatic target (e.g., COX-1 versus COX-2) is not established, and is further complicated by the fact that NSAIDs can have actions on signaling pathways distinct from the generation of prostanoids. Although no complete picture has yet emerged, the following sections summarize current data that impact on our understanding of NSAID benefits in AD. Additional perspectives on this subject can be found in a number of recent review articles [114,115,182,197–199].

3.2.1. Evidence from animal models Studies in several different animal model systems indicate that neuroinflammation can be attenuated by NSAIDs. For example, indomethacin partially suppressed microglial activation in rats infused intraventricularly with Ab [200]. In another model, chronic infusion of lipopolysaccharide (LPS) into the basal forebrain of rats was associated with robust microglial activation and expression of inflammatory mediators, degeneration of basal forebrain cholinergic neurons, and behavioral deficits in spatial memory tasks [201–203]. In animals treated with CI987, a combined COX-2 / lipooxygenase inhibitor, microglial activation was attenuated as was the loss of cortical acetylcholine content [203]. In another model of basal forebrain degeneration, injection of quisqualic acid in the nucleus basalis led to cholinergic degeneration, microglial activation, and increased production of IL-1b and PGE 2 [69]. Treatment with nimesulide, an NSAID that inhibits COX-2, resulted in reduced numbers of activated microglia and reduced production of IL-1b and PGE 2 . A similar decrement of inflammation related mRNAs has been observed in mice subject to cortical radiation injury and treated with the COX-2 inhibitor, NS-398 [204]. A number of reports have demonstrated glial activation and expression of inflammatory mediators in transgenic mice overexpressing mutant human APP genes [142,205–207]. In mice overexpressing the Swedish mutation of APP (Tg2576), 6 months of treatment with ibuprofen starting at 10 months of age when plaques first appear, led to a decrease in IL-1b and GFAP levels, number of plaques, and number of ubiquitin-positive neurites [208]. Although these results suggest that ibuprofen, an inhibitor of both COX-1 and COX-2, reduces the inflammatory re-

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action to Ab deposition, the formal possibility that it does so indirectly by influencing the deposition process itself has not been excluded. Brain or spinal cord trauma results in induction of COX-2 [209–211]; however, the benefits of COX-2 inhibitors in traumatic CNS injury are mixed (reviewed in Ref. [212]). COX-1 may also play a role in CNS injury. For example, prolonged accumulation of COX-1 positive microglia and macrophages was observed following traumatic brain injury in rats [213]. Thus, microglial COX-1 may be a relevant target for therapeutic intervention. COX-2 is induced in ischemic brain injury and in seizures [196,214–216]. Several studies have reported the effects of COX-2 inhibitors on outcome in these models. In general, COX-2 inhibition appears to be neuroprotective in ischemia: infarct area is reduced in both global and focal ischemia models [216–218]. Moreover, use of a COX-2 inhibitor resulted in attenuation of behavioral deficits in a rabbit model of spinal cord ischemia [219]. The data for seizure models is less consistent: some reports show neuroprotection [220], while others suggest that hippocampal damage is aggravated by COX-2 inhibition [221]. Mechanisms underlying protection by COX-2 inhibitors in ischemic injury may include direct neuroprotective as well as longer-term anti-inflammatory actions. With regard to neuroprotection, COX-2 null mice showed decreased damage to focal ischemia and direct cortical injection of N-methyl-Daspartate (NMDA); similar results were observed in wild-type mice treated with NS-398 [222]. Additional evidence for direct neuroprotection is provided by in vitro demonstration that COX-2 inhibitors decrease cortical neuron death due to NMDA toxicity [223]. Neuroprotection by COX inhibitors may also arise indirectly since prostaglandins have been shown to potentiate glutamate release from astrocytes [224,225]. A more thorough discussion of potential mechanisms for neuronal injury can be found in a recent review [114]. It is worth noting that NSAIDs have been shown to be beneficial in animal models of several neurodegenerative diseases. For example, aspirin and salicylate protected dopaminergic neurons from 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice [226]. Interestingly, several other NSAIDs

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did not attenuate MPTP toxicity in this study, suggesting that the effects were due to actions other than COX inhibition (see Section 3.2.3). In a later study, high dose aspirin as well as meloxicam were shown to attenuate MPTP damage [227]. Other investigators have reported increased COX-2 expression and PGE 2 levels in amyotrophic lateral sclerosis as well as in a mouse model of the disease [228,229]. Studies in a spinal cord organotypic model of ALS suggest that COX-2 inhibition protects motor neurons [230]. Whether such findings result from direct neuroprotection versus anti-inflammatory roles of the COX-2 inhibiting drugs remains to be determined.

3.2.2. Cyclooxygenases in AD Based on clear evidence for localized tissue inflammation in AD brain and data indicating that NSAIDs are beneficial in AD, a number of studies have been undertaken to establish levels and cellular localization for cyclooxygenase isoforms in AD brain. Surprisingly, a general consensus has not been readily established. Factors contributing to this problem include evidence that COX-2 mRNA is relatively unstable in human postmortem brain [231], differences in antibodies and quantitative measures employed by various investigators, differences in cases and brain regions examined, and as mentioned previously, the significant degree of cyclooxygenase expression in normal tissue. With regard to COX-2, reports of mRNA levels in AD have included decreased [232], increased [233,234], and highly variable [231]. Several studies report increased levels of COX-2 protein in AD brain, largely attributed to increased neuronal expression [233,235–238]. Interestingly, one group reported increased staining intensity for COX-2 in hippocampal neurons as a function of clinical dementia rating [239]. In contrast, a study of control and AD tissue collected prospectively and employing a method of tissue fixation specifically for COX-2, demonstrated a reduction in AD of the percentage of neurons expressing COX-2 in all hippocampal subfields [240]. Moreover, in contrast to previous work suggesting that COX-2 was preferentially expressed in NFT bearing neurons, this later study showed a negative correlation with the presence of tangles. Finally, the percentage of neurons expressing COX-2 in cases with other dementia was also diminished

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relative to control tissue. Taken all together, these findings suggest that COX-2 is robustly expressed in normal human hippocampus (70–80% of neurons in most fields) and that AD and other dementia lead to a decreased percentage of neurons expressing COX-2, perhaps secondary to a loss of synaptic connections [240]. Importantly, these conclusions are restricted to end stage disease, which far and away represented the predominant type of tissue in this prospective analysis. Thus it may be that COX-2 levels are increased and contribute to the disease process early on, but are less relevant late in the disease. It is worth mentioning that a few authors have noted COX-2 expression in astrocytes and vascular elements in AD [240] similar to reports in transgenic mice harboring APP mutations [142,241]. However, it is clear that neurons represent that principal reservoir of COX-2 in human brain. Fewer investigators have examined COX-1 expression in AD. Levels of COX-1 protein and mRNA appear to be modestly increased in AD [236]. Interestingly, COX-1 appears to be constitutively expressed by the majority of microglial cells in normal brain, as evidenced by data in mouse, rat, primate, and human brain [242]. Increased density of COX-1 expressing microglia in AD cortex and their association with Ab plaques suggests that COX-1 may well contribute to inflammatory processes in the disease [238,242]. Indeed, findings that the number of activated microglia associated with senile plaques is decreased in nondemented individuals who use NSAIDs provides evidence that microglial COX-1 is a target for NSAIDs in human brain [243]. However, this data contrasts with a small study of AD and control brain tissue comparing users of NSAIDs to nonusers that showed no significant alteration in neuropathology or degree of microglial activation with NSAIDs, despite a significant benefit of NSAIDs on cognitive function [244]. COX-1 is also expressed in human hippocampal neurons, but is limited to CA3 and hilar neurons that are less affected than other hippocampal regions in AD [242]. Evidence that cyclooxygenase expression may be elevated in AD is further supported by findings that PGE 2 levels are substantially increased in cerebrospinal fluid from AD patients [118,119]. Interestingly, levels of another prostanoid (6-keto-PGF 1a ,

the major metabolite of PGI 2 ) were decreased in AD CSF [119]. In the same study, cyclooxygenase activity measured in hippocampal samples from AD patients was not different from control subjects. Whether COX activity in other brain regions or changes in enzymes responsible for synthesis of the different prostanoids (see Section 3.2.4) account for increased PGE 2 in CSF remains unknown.

3.2.3. Other potential actions of NSAIDs In addition to their principle action as inhibitors of cyclooxygenase, at least some NSAIDs have been shown to have other anti-inflammatory properties. The two major mechanisms, activation of the peroxisome proliferator-activated receptor-g (PPARg) and inhibition of the nuclear factor (NF)-kB pathway are discussed below. The PPARs are members of the steroid / thyroid superfamily of nuclear hormone receptors. Acting in concert with the retinoid X receptor, upon ligand binding PPARs direct transcription in the nucleus (reviewed in Ref. [245]). One ligand of PPARg is 15-deoxy- 12 ,14 -prostaglandin J 2 (15-d-PGJ 2 ) a potential metabolite of PGD 2 . Although first described in adipocyte differentiation [246,247], 15-d-PGJ 2 has also been shown to downregulate macrophage activation by inflammatory mediators [248,249]. Importantly, some NSAIDs are ligands for PPARg [250] and may exert anti-inflammatory effects by this mechanism [249]. These effects extend to cells of the CNS. For example, iNOS induction in glial cells is attenuated by 15-d-PGJ 2 and other PPARg agonists [251] and these compounds (including some NSAIDs) have been shown to reduce inflammatory mediators and neurotoxic signals generated by monocyte / microglial cells exposed to Ab, cytokines, or LPS [93,252]. Interestingly, indomethacin, ibuprofen and 15-d-PGJ 2 inhibited iNOS induction and resultant neurotoxicity in cerebellar granule cell cultures exposed to LPS and proinflammatory cytokines [253]. In a later report, these findings were replicated in vivo: treatment with ibuprofen, 15-d-PGJ 2 , and a specific PPARg agonist (troglitazone) resulted in neuroprotection of cerebellar granule neurons in rats intracerebellarly injected with LPS and g-interferon [254]. Importantly, the COX-2 inhibitor NS-398 had no neuroprotective effect in this same model. It is worth noting that there is some controversy about

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whether anti-inflammatory actions of 15-d-PGJ 2 are solely through its interaction with PPARg [255–257]. Nevertheless, the use of thiazolidinediones, which are known to be PPARg agonists and currently used as anti-diabetic drugs, has been suggested for AD [258]. The NF-kB signaling cascade is a major pathway for altering gene expression in response to inflammatory mediators. Activation of this pathway depends on phosphorylation dependent removal of an inhibitory subunit called IkB from the transcription factor NF-kB. Several NSAIDs, including aspirin, salicylate, and sulindac, appear to downregulate NF-kB activation in response to inflammatory mediators by inhibiting the actions of the b subunit of IkB kinase [259,260]. As one example relevant to AD, sodium salicylate was shown to inhibit NF-kB activation in astrocytes exposed to Ab and LPS [261]. Although the mechanism underlying their action is not as well understood, several other NSAIDs, including ibuprofen and flurbiprofen, have been shown to inhibit NF-kB activity [262,263], albeit at doses larger than required for COX inhibition. Interestingly, cyclopentanone prostaglandins such as 15-d-PGJ 2 may exert their anti-inflammatory effects by inhibiting IkB kinase [264]. Finally, a potential mechanism for the effectiveness of NSAIDs in AD independent of effects on inflammation or cyclooxygenase has been proposed [265]. In vitro and in vivo studies with various doses of commonly used non-selective NSAIDs showed that a subset of NSAIDs (ibuprofen, indomethacin and sulindac sulphide) may influence amyloid pathology by decreasing the production of Ab 1 – 42 , the isoform of the Ab peptide that is associated with aggregation. These results were observed in fibroblasts deficient of COX-1 or COX-2, suggesting that COX inhibition is not involved in this altered processing of APP. Instead, the authors suggest that this subset of NSAIDs shift the activity of g-secretase to favor production of Ab 1 – 38 [265].

3.2.4. Other targets in the prostaglandin pathway Although inhibiting cyclooxygenase remains the mainstay of therapies aimed at attenuating prostaglandin signaling, it is clearly not the sole target. For example, generation of arachidonic acid substrate for prostanoid generation is largely dependent on phos-

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pholipase A 2 . Despite the existence of many PLA 2 types (reviewed in Refs. [266,267]), only a few, including the secreted type II and the 85-kDa cytoplasmic PLA 2 (cPLA 2 ), have been linked to prostanoid production in inflammation. Because of their unique patterns of expression and cellular localization, coupling between PLA 2 and COX isoforms has been recognized (reviewed in Ref. [268]). With regard to AD, immunostaining for cPLA2 is increased in AD brain relative to control and is largely restricted to astrocytes [269]. In a later study, this same group showed that cPLA 2 was upregulated in astrocytes and less consistently in microglia in a wide variety of neurodegenerative paradigms, including ischemia, facial nerve axotomy, AD, and transgenic models of ALS and AD [270]. Importantly, detection of cPLA 2 was correlated with areas of neuronal degeneration. Moreover, genetic deletion of cPLA 2 is associated with attenuation of injury in middle cerebral artery occlusion and MPTP toxicity models [271,272]. Although the evidence is intriguing, additional studies with relatively selective inhibitors of cPLA 2 or with knockout mice will be required to more firmly establish the potential use of such agents in treatment or prevention of AD. The immediate product of COX activity, PGH 2 , is rapidly isomerized to final prostanoid products by tissue specific enzymes. Interest in selectively inhibiting production of PGE 2 , the principle inflammatory prostanoid, has been heightened by recognition of at least two PGE 2 synthase isoforms that are apparently coupled to distinct COX isoforms. More specifically, a membrane-associated isoform (mPGES) is functionally coupled to COX-2, whereas a cytosolic enzyme (cPGES) appears to be linked to COX-1dependent PGE 2 production [273,274]. Although cellular localization may play some role, functional coupling is largely a factor of expression patterns: like COX-2, mPGES is dramatically upregulated by proinflammatory stimuli [273,275] while cPGES seems to be relatively constitutively expressed [274], at least in the cell systems examined so far. COX-2 and mPGES are coordinately upregulated in brain endothelial cells during fever induction by LPS [276] as well as in a rat model of adjuvant arthritis [277]. Intriguingly, Ab has been shown to induce expression of mPGES in rat astrocytes [278]. If such results hold in other systems, development of drugs that

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target mPGES may represent a new and powerful anti-inflammatory approach that may be applicable to AD. Finally, prostanoid effects are mediated by binding to specific receptors, with the best characterized being a family of G-protein coupled transmembrane receptors (reviewed in Ref. [279]). Thus, development of specific antagonists for individual receptors can be considered. Indeed, such antagonists have been developed for the thromboxane receptor and are useful for anti-platelet therapy [280]. However, the existence of four distinct PGE 2 receptor genes, as well as several splice variants, makes this approach challenging for development of compounds with anti-inflammatory effects.

3.3. Anti-inflammatory actions of other drugs 3.3.1. Estrogen Estrogen replacement therapy (ERT) in postmenopausal women may be beneficial in prevention or treatment of AD. Epidemiological studies have shown that ERT is associated with improvement in cognitive performance, protection against cognitive decline, and a decreased incidence of AD [281–286]. Results from clinical studies are mixed. Several studies show selective cognitive improvement in demented women receiving ERT [287,288]. However, these studies were of relatively short duration and are consistent with improved cognitive performance seen with ERT in non-demented postmenopausal women as well as in ovariectomized rats [289– 291]. More recently, a year-long investigation of ERT in postmenopausal women with mild to moderate AD showed no benefit in halting cognitive and functional decline [292]. Whether ERT is beneficial for early treatment or prevention of AD remains an open question. A variety of mechanisms have been proposed to account for the potential beneficial effects of estrogen on cognitive function in aging and demented women. Animal studies reveal potent effects of estrogens on dendritic plasticity, neurogenesis, and learning (reviewed in Ref. [291]). Moreover, neuroprotective effects have been described for estrogen in models of stroke, oxidative stress, and excitotoxicity [293–296]. Similar findings of neuroprotection to Ab toxicity suggest a possible mechanism of action

related to AD [297–300]. Interestingly, estrogen can also influence production and processing of Ab peptides in neuronal cultures [301]. Finally, estrogen appears to protect women against cardiovascular disease and stroke [295,302]. These vascular effects may be associated with protection from AD since dementia is strongly influenced by concurrent cerebrovascular disease [303]. More recently, the possibility that estrogen exerts anti-inflammatory actions in brain has been explored. For example, estrogen blocks microglial activation, as measured by superoxide release, nitric oxide production, and phagocytic activity induced by LPS and several other agents [304]. Interestingly, these effects occurred with low doses of estrogen ( | 1 nM) and were blocked by inhibitors of the p42 / 44 MAP kinase pathway. In another study, low levels of estrogen blocked LPS-mediated induction of matrix metalloproteinase-9, inducible nitric oxide synthase, and PGE 2 production in primary cultures of rat microglia [305]. Based on these findings, the antiinflammatory actions of estrogen may represent an important mechanism underlying the influence of estrogen on AD. It would be interesting to test whether estrogen attenuates the inflammatory response to Ab deposition seen in transgenic mouse models.

3.3.2. Vitamin E and other anti-oxidants As already discussed, oxidative damage, likely enhanced by inflammatory reactions, is clearly evident in AD brain and may play a significant role in the pathogenesis of neuronal degeneration (reviewed in Ref. [306]). Interestingly, oxidative changes, revealed by increases in the lipid peroxidation products known as F2-isoprostanes, appeared prior to detection of Ab deposition in transgenic mice [134]. Inflammatory responses are also modulated by oxidant stress. For example, vitamin E reduces the reactive phenotype of cultured microglia [307] and an age-associated increase in PGE 2 levels and cyclooxygenase activity was partially mitigated by vitamin E treatment [308]. Regardless of the sequence of events and the relative contribution of brain inflammation to oxidative damage and vice versa, a muticenter, placebo-controlled trial of vitamin E in AD showed some benefit [309]. Additional trials of antioxidant therapies, perhaps in combination with

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more traditional anti-inflammatory therapies, seem warranted.

4. Clinical trials of anti-inflammatory drugs in Alzheimer’s disease Evidence for inflammation-related changes in AD brain and benefits of NSAIDs in disease treatment and prevention have spurred several clinical trials of anti-inflammatory drugs in AD. Despite the preponderance of evidence supporting a preventative role for anti-inflammatory therapies, most current trials address utility of anti-inflammatory agents in treatment of disease, a possibility suggested by only a few studies [310,311].

4.1. Nonsteroidal anti-inflammatory drugs Results from a small placebo-controlled trial of diclofenac, a mixed COX-1 / COX-2 inhibitor have been reported [312]. An interesting feature of this study was the administration of diclofenac combined with misoprostol, a prostaglandin E 2 analog that confers some protection to the gastric mucosa. Despite this strategy, 12 of 27 AD patients started on drug dropped out of the study versus two of 17 in the placebo group. Ultimately, only 12 patients completed the full 25-week course of therapy. Although there were modest trends for the diclofenac group to show less deterioration relative to controls on several outcome measures, none of these reached statistical significance, probably related to the small group size. A large multicenter trial of the COX-2 selective inhibitor celecoxib versus placebo was completed in 1999. This study enrolled over 400 AD patients at sites in Europe and the United States. Duration of treatment was 6 months and, though specific details are not available, primary outcomes were measures of cognitive capacity. Despite the large number of AD patients entered in this trial, no difference in rate of cognitive decline was found between the celecoxib-treated and placebo groups [313]. Note that trials of similar size, duration, and population revealed benefits of acetylcholinesterase inhibitors in AD [314,315]. A definitive trial using a nonselective (naproxen) and a COX-2 selective NSAID (rofecoxib) for treat-

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ment of AD is nearing completion [316]. The duration of treatment will be 1 year with an anticipated enrollment of 320 patients with mild to moderate AD. This study should provide a final answer to the question of whether NSAIDs are effective in slowing the progression of AD. As already mentioned, the preponderance of evidence points toward the possibility that NSAIDs prevent or delay the onset of AD. A major challenge in designing preventative trials for AD is selection of a patient population with some degree of risk for the disease. A trial of rofecoxib for prevention of AD is currently in progress and approaches this issue by selection of subjects with mild cognitive impairment (MCI). The outcome will be people progressing to a clinical diagnosis of AD. MCI is characterized as memory impairment beyond what is appropriate for age, with relative preservation of other cognitive domains and normal ability to perform activities of daily living [317]. Long-term follow-up of individuals with MCI indicates progression to AD in about 15% of individuals each year [318]. Thus, this group has a relatively high and predictable rate of progressing to AD, though some individuals may never be affected [319]. Funded by the National Institute of Aging (NIA), a prospective, primary prevention study now underway employs a population consisting of 2625 individuals, 70 years of age and older, at high risk for the disease based on having at least one first-degree relative with AD. Individuals with a diagnosis of MCI will not be entered into the study. This population is clearly unique from the MCI group, so results from the two preventative trials will not be directly comparable. The study is designed to run 7 years, but formal interim analyses will be conducted to evaluate efficacy as the trial progresses. Importantly, this trial will evaluate the effects of a traditional inhibitor (naproxen) as well as a COX-2 selective inhibitor (celecoxib).

4.2. Other anti-inflammatory drugs Results of an NIA sponsored trial of low-dose prednisone for the treatment of Alzheimer’s disease have been published [320]. Despite known problems with long-term therapy, this trial was undertaken because of the potential benefit afforded by the broad

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anti-inflammatory and immunosuppressive actions of glucocorticoids. The treatment regimen consisted of 20 mg prednisone qd for 4 weeks, 10 mg prednisone qd for 1 year, followed by a slow tapering dose over 16 additional weeks. Of 138 patients originally randomized to the study, 50 subjects in the prednisone group and 58 in the control group completed the study. There was no difference in cognitive decline between the two groups. However, the prednisone group had greater increases in Blessed Dementia Rating Scale subscores reflecting agitation and hostility / suspicion [320]. Propentofylline, a phosphodiesterase inhibitor with neuroprotective and glial modulatory actions [321], has been utilized in several clinical trials with AD and vascular dementia patients [322]. Although some studies have suggested that propentofylline can downregulate glial activation and expression of inflammatory mediators [323–326], it is not know whether these or more direct neuroprotective actions are responsible for the possible benefits observed in early clinical trials. Based on their use as anti-inflammatory agents for diseases of the joints as well as some evidence for neuroprotective and anti-amyloidogenic properties, hydroxychloroquine and colchicine have been proposed as potential agents for treatment of AD [327]. Results from a pilot study indicate that subjects with probable AD tolerated hydroxychloroquine alone or combined with colchicine for up to 12 weeks [328]. No significant effects on cognition or behavior were noted in the small number of subjects tested; a larger study will clearly be needed to determine whether this approach is valid.

5. The potential protective role of inflammation in Alzheimer’s disease Throughout most of this review, inflammation associated with AD has been discussed as a contributor to the disease process and potential target for therapeutic intervention. However, this view must be tempered by consideration of the possibility that glial activation and inflammation-related changes in AD brain play a significant role in maintenance of function or repair of damage. Ultimately, the aim of therapy might be to strike a balance between repara-

tive and damaging functions. Many cytokines have been shown to have protective roles. For example, IL-1b knockout mice show poor remyelination following exposure to cuprizone [329], whereas TNF receptor knockout mice show greater damage following stroke [330]. With respect to cyclooxygenase, expression of COX-2 inhibits apoptosis of PC12 cells in an NGF-withdrawal paradigm, apparently by reducing neuronal nitric oxide synthase activity [331,332]. The possibility that anti-inflammatory prostaglandins such as 15-d-PGJ 2 might be reduced by NSAID therapy needs to be considered [333]. For example, delayed administration of the COX-2 inhibitor NS398 in a model of lung pleurisy resulted in increased inflammatory exudate [334]. PGE 2 itself can have anti-inflammatory effects. For example, PGE 2 downregulates IL-1b production in rat microglia responding to LPS [335,336]. Moreover, intracerebral injection of PGE 2 attenuated local expression of TNFa and IL-1b associated with the needle tract, and reduced microglial activation in response to systemic LPS treatment [121]. Finally, demonstration that vaccination with Ab can prevent or attenuate amyloid deposition as well as cognitive deterioration in transgenic mouse models implies that the immune system has the potential of playing a very significant role in AD pathology and pathogenesis [337–339]. It has been suggested that the mechanism underlying the benefits of vaccination involve opsonization of Ab by antibodies and phagocytosis by resident microglia [339]. Despite their clear association with Ab plaques, the extent to which microglia phagocytize Ab during the normal course of disease is controversial. Nevertheless, inhibition of microglial function by anti-inflammatory approaches may prove detrimental, particularly in the setting of an antibody response mounted to Ab. Examination of transgenic, vaccinated mice treated with NSAIDs and other agents will help to clarify this important issue.

6. Summary As highlighted in this review, a multitude of cellular responses and inflammatory mediators have been identified as playing potential roles in AD

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pathogenesis. Over the past decade, the science of neuroinflammation in AD has moved from a simple categorization of expressed molecules in AD pathology to studies aimed at roles and interactions in disease pathogenesis. New model systems, in particular transgenic mice overexpressing mutant human APP genes, have proven invaluable in sorting out contributions for each of these factors. Along these lines, studies where transgenic lines are crossed so that several genetic changes are examined together have been particularly fruitful. Nevertheless, findings from these experiments, as well as those arising from careful examination of mechanisms using in vitro cultures, do not provide absolute evidence for therapeutic intervention in the disease. Nor do they faithfully reproduce the long and insidious course of pathological changes that appear to precede clinical disease by decades. For the larger question of potential benefit in patients, the epidemiological and clinical data point toward the use of NSAIDs for prevention and possibly treatment of AD. Despite this evidence, early clinical trials with promising drugs have failed to show pronounced benefit. Whether this is due to poor target choice or the lateness of treatment relative to pathological state is unknown, but will be sorted out by studies currently in progress. So where does neuroinflammation lie in the pathogenesis of AD? Based on evidence discussed in this review, a relatively simple scheme places glial-directed neuroinflammation after, but influencing Ab deposition (Fig. 1). Neuroinflammation alone or in combination with direct effects of Ab leads to kinase activation, oxidative damage, neuronal dysregulation and death, which ultimately give rise to the progressive dementia that typifies AD. Based on this scheme, intervention with anti-inflammatory therapies may attenuate the process, in effect partially or wholly uncoupling early alterations in Ab homeostasis from neuronal damage and dementia. This hypothesis can now be tested with available animal model systems. Equally important is the extent to which anti-inflammatory therapies influence other intervention strategies, notably vaccination with Ab peptide. Establishing the relative benefits, costs, and interactions of these and other strategies will represent a major goal of AD research in the coming years.

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Fig. 1. Neuroinflammation and AD pathogenesis. This model assumes a primary defect in APP processing, a known factor for familial AD. Whether this applies in sporadic AD in not known. Modified from Ref. [40].

Acknowledgements Our work has been supported by grants from the National Institute of Health (NS33553, AG08665 and CA11051), the Alzheimer’s Association (1999PRG-1851) and the Lucille P. Markey Charitable Trust.

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