The Role of the Immune System in Alzheimer's Disease
Abstract
The accumulation of toxic products (TP) of the processing of the amyloid precursor protein is the likely initial event in a “cascade of events” that leads to Alzheimer's disease (AD). The immune system is, however, attracting the increasing attention of researchers working in this area. First, as a responder to and possible contributor to the pathological events that occur in AD, second as a modifier of the production of and clearance of TP, third as part of a system of neuroprotection, and fourth as a suitable target in designing AD treatment strategies. While still at an early stage of understanding these complex, multidimensional, and at times, conflicting roles of the immune system in AD it is likely that successful AD treatment strategies will need to carefully consider and account for the immune network within the overall design.
Alzheimer disease (AD) is believed to result from an abnormal processing of the amyloid precursor protein (APP) that leads to the accumulation of “toxic products” (TPs), most notably β-amyloid (1). There is, however, a growing recognition that the immune system may modulate APP processing, TP clearance, the cellular responses to TPs, and, therefore, that the immune system may serve as a valuable entry point for treatment (1–5). Nevertheless, considerable uncertainty remains about the exact role of the immune system in AD (2, 3). Most efforts to understand the role of the immune system and vaccines that target β-amyloid for AD treatment have focused on inflammation and the role of activated microglia in secreting cytokines and in the phagocytosis and clearing of the TPs of APP processing. More recently, however, it has become apparent that T cells, another cellular component of the immune system, found in increased numbers in postmortem brains of patients with AD (6, 7) may play an important role in regulating microglia activation and function (8).
AD PATHOPHYSIOLOGY
Central to our understanding of AD and its treatment are the pathological features of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) (9), the most important components of which are β-amyloid (1, 10–11) (Aβ1-40 and Aβ1-42 or Aβ) and hyperphosphorylated tau (12–15), respectively. For some years the field was split between those who believed that β-amyloid (amyloid hypothesis) was the trigger that was responsible for the neurodegeneration and those who believed that the trigger was abnormal tau (tau hypothesis). The findings that genetically dominant early-onset forms of AD resulted from mutations in APP, presenilin 1, and presenilin 2 substantially altered the debate. Mutations in all three genes could be shown to lead to variations in the processing of APP, resulting in increased concentrations of Aβ1-40 and Aβ1-42 and/or a shift in their ratio favoring the formation of Aβ1-42. Aβ1-42 was demonstrated to have greater toxic potential because of its greater propensity to form oligomers and fibrilized forms (16). However, it is yet to be determined which of the various combination of products and aggregates of the APP processing pathway as well as their location, i.e., intracellular or extracellular, are the chemical moieties and pathways that most directly affect neuronal damage in AD (17–21).
DOES THE IMMUNE SYSTEM CONTRIBUTE TO AD PATHOLOGY?
There is increasing evidence that the mere accumulation of β-amyloid (Aβ1-40 and Aβ1-42 and all their forms including diffuse amyloid plaques and NPs) may not be sufficient to induce the cognitive findings of AD and that the immune system may play a critical role in the clinical symptoms. Activated microglia and astrocytes, cellular components of the brain's immune network, are found in close proximity to senile plaques (22–25). Elevated levels of both pro- and anti-inflammatory cytokines, e.g., interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein are found in the plasma and/or cerebrospinal fluid of patients with AD (26–29). Evidence of complement activation is also found in the AD brain (30) together with increased numbers of brain T cells, primarily of the CD8+ type (6, 7).
Despite the fact that the above findings were reported some time ago, the absence of a leukocyte infiltration diminished interest in the role of the immune system and neuroinflammation in AD. It was not until findings from several epidemiological studies suggested that anti-inflammatory drugs, particularly nonsteroidal anti-inflammatory drugs, reduce the risk of developing AD that interest developed in the possible causative role of neuroinflammation in the clinical symptoms of AD (31–34). Subsequent support for the importance of the immune system in AD pathology derives from the findings that polymorphisms in genes that are part of inflammatory pathways are associated with altered risk of AD (35–41) and from neuroimaging studies using labeled PK1195 (1-[2-chlorphenyl]-N-methyl-N-[1-methyl-propyl-]-3-isoquinoline carboxamide) (42, 43). PK1195 is a tracer that binds to the peripheral benzodiazepine receptor, a receptor found on activated microglia cells, cells normally present in very small numbers in the brain. An increased accumulation of the tracer has been found in entorhinal and temporoparietal cortices and the posterior cingulate of even mildly affected patients with AD. Unfortunately, however, trials of anti-inflammatory agents in AD have not shown efficacy (33, 34).
If the toxic products of APP processing are what results in AD, what are the possible mechanisms for immune system modification of clinical symptoms? Postmortem findings have suggested that clinical manifestations of AD are most closely tied to regional accumulation of NFTs rather than NPs and loss of synapses even more than NFTs (44–48). Studies of neuronal damage reveal that inflammation can modify or accelerate APP production and tau phosphorylation (49–54). Further, individuals known to be healthy before their death can have substantial amounts of β-amyloid found at postmortem (55–61), but these brains usually do not display the typical neuroinflammatory markers of AD (62). In addition, subjects with possible as well as early AD at postmortem show substantial numbers of activated microglia (63–65), suggesting that neuroinflammation can occur early in the disease process.
Further, Toll-like receptors (TLRs) have been linked to the pathogenesis of AD and TLRs 1, 2, 4, 5, 7, and 9 and CD14 are up-regulated in the aging mouse brain (66, 67). Both TLRs and CD14 are membrane proteins found on cells that are part of the immune system. In this context, it is of some significance to note that the immune system consists of two networks, the innate and the adaptive. Initiation of the innate network response occurs through the recognition of “pathogen-associated molecular patterns” that are produced by microorganisms. In general, recognition relies on interaction with TLRs and inflammation on downstream signaling to activate the transcriptional factor nuclear factor-κB that leads to increased transcription of proinflammatory genes.
Recent studies with positron emission tomography using amyloid tracers have shown that some 10%–15% of older healthy individuals have amyloid tracer accumulations that overlap with those of patients with AD and that even a higher percentage was seen in those with mild cognitive impairment (68–72). Thus, the amyloid tracer data are consistent with other neuroimaging and cognitive data, suggesting that changes in brain physiology in individuals at risk for AD may begin decades earlier than the expected clinical manifestation of the disorder (73–81) and that β-amyloid accumulation is not always immediately toxic.
CONCLUSIONS
Although abnormal amyloid processing is central to AD pathology, additional factors must contribute to the onset and progression of clinical symptoms that are more directly related to NFT and synapse dysfunction and loss. On the basis of animal models and association studies in humans, the immune system is likely to be one of the critical contributors to tangle formation and synapse dysfunction through inflammatory processes and modification of APP processing.
POSSIBLE MOLECULAR AND CELLULAR MECHANISMS OF CONTRIBUTIONS OF THE IMMUNE SYSTEM TO AD PATHOLOGY
In vitro studies and studies in animal models have provided evidence for the molecular and cellular mechanisms possibly involved in the contribution of the immune system to AD pathology. Until now most efforts to understand the role of the immune system have focused on inflammation and the role of activated microglia.
MICROGLIA
The immune network depends on specialized cells in every tissue or organ to provide surveillance for potentially foreign agents, to signal to the rest of the immune system cells their presence, and to remove debris. Microglia are brain macrophages that function in phagocytosis, recruitment of T cells, and presentation of antigens (82). At rest these highly ramified cells can surveil up to 50 μm of extracellular brain tissue with some overlap between microglia through a continuous extension and retraction of processes at speeds up to 1.5 μm/min. When activated microglia release complement proteins and inflammatory cytokines, such as IL-1 and IL-6, chemokines, reactive oxygen species, nitric oxide, TNF-α and IL-1β, and matrix metalloproteinases. These released products have been demonstrated to have a direct role in neural damage in cocultures of activated microglia and neurons as well as in AD mouse models (30, 34, 83, 84).
Neurodegeneration as, for example, occurs in the AD brain can cause microglia to be activated. Microglia can also be directly activated by the binding of Aβ (85, 86) as well as by the costimulatory molecules CD40/CD40 ligand (CD40L), found to be increased in AD and animal models of AD (87, 88). Further, CD40/CD40L have been shown to promote pathological changes (amyloid load, gliosis, and hyperphosphorylation of tau) in animal models of AD and, along with IL-1, promote the up-regulation of APP expression (87, 89–92). Aβ, however, is also capable of directly activating the complement system through the classic and alternate pathways by binding C1q and C3b (30, 86). The activated complement system is capable of inducing damage to healthy tissue. Moreover, degenerating neurons and oxidative stress induced by Aβ may also serve as secondary triggers of inflammation with the inflammatory process itself triggering increases in apolipoprotein E and α-1-antichymotrypsin that, in turn, can promote Aβ deposition (93, 94).
Although inflammation in the brain is generally considered harmful because of the damage it can do to healthy cells, data suggest that some components of the inflammatory process may be protective in the amyloid-burdened brain. For example, in an AD rodent model with increased expression of a soluble complement receptor-related protein y that inhibits complement activation, there is a marked increase in Aβ accumulation (95). Further, microglia can secrete enzymes that degrade Aβ (96, 97) and can also phagocytose Aβ (85, 98–102). Additional support for a protective role for microglia derives from experiments in which lipopolysaccharide infusions have increased amyloid clearance in an AD mouse model, presumably as the result of increased phagocytosis (103). Similarly, one likely mechanism whereby active and passive immunization against Aβ (see below) clears brain amyloid is through an increase in microglia phagocytosis (2, 3, 105).
This diversity in action of activated microglia has led to the idea that microglial activation exists on a continuum from “innate activation,” characterized by phagocytic response on one end, and “adaptive activation,” characterized by antigen-presenting cell function with expression of class II major histocompatability complex (MHC II) proteins on the other. Where along the continuum activation occurs is determined by the specific stimulatory and costimulatory environment (105–110). For example, the above mentioned CD40-CD40L interaction leads to adaptive activation and away from innate activation. Th1 type “regulatory or anti-inflammatory cytokines” (IL-4, IL-10, and transforming growth factor-β) also tip activation of microglia toward the antigen-presenting cell continuum, whereas Th2 type “proinflammatory cytokines” (interferon-γ, TNF-α, and IL-6) shift the activation back toward innate activation. It is important to note, however, that although activation by Aβ1–40 or lipopolysaccharide can lead to increased phagocytosis, the activated microglia can also be toxic to neurons and impair neural cell renewal (111).
Conclusions.
Microglia are pivotal cells in the immune response to abnormal APP processing with studies suggesting that activation of microglia may occur along more than one dimension. Further complicating the issue is the fact that the nature of the microglial response may depend on the brain region involved, the amount and rate at which neuronal damage is occurring, the condition of the blood-brain barrier, and the presence of other factors influencing the innate immune system. Moreover, it is possible that the senescence of microglia as individuals age that results in a reduced capacity of microglia to phagocytose amyloid as well as secrete neuroprotective growth factors may contribute to both age-related cognitive changes as well as to AD risk (87, 112, 113). Unfortunately, very little is known about the effect of age on microglial function in AD animal models and even less about the role of astrocytes and T cells, the two other common cell types that are part of the brain's immune system.
T CELLS
Although the number of T cells that enter the healthy brain is substantially less than that in other organs, T lymphocytes that have been stimulated to the blast phase are capable of entering the central nervous system (CNS) presumably in search of antigens. Inflammation or tissue damage enhances neural entry of T cells (114–116). T cells that enter the healthy CNS find an environment that is not conducive to their survival although the mechanisms are unknown. However, if presented with antigen, T cells in the CNS are capable of accumulating. One of the most exciting recent findings has been the discovery of the capacity of activated T cells to secrete neurotrophic factors that foster repair of damaged tissue in the CNS. This well-controlled antiself-response may help the body resist neurodegeneration, i.e., a form of protective autoimmunity (106, 107). The response has been demonstrated to be mediated by autoimmune T cells that produce cytokines and growth factors that activate microglia to produce growth factors that are neuroprotective, e.g., insulin-like growth factor-1. IGF-1 increases Aβ removal through the choroid plexus, stimulates neurogenesis, and through a variety of intracellular pathways inhibits glycogen synthase kinase 3β, an enzyme that plays a role in phosphorylating tau (117, 118).
Three new treatment approaches recently evaluated in AD mouse models emphasize the critical role of T cells in regulating the immune system response as well as microglia activation in the amyloid-burdened brain. Ethell et al. (119) transferred T-cell enriched populations of Aβ-specific immune cells from nontransgenic littermates into cognitively impaired AD mice. The adoptive transfer reversed cognitive decline and synaptic loss for at least 2.5 months after a single infusion. Butovsky et al. (120) exposed T cells in vitro to glatiramer acetate, a U.S. Food and Drug Administration-approved synthetic copolymer resembling aspects of myelin used in the treatment of multiple sclerosis, before infusing them back into an AD mouse model. The reduction in amyloid load and restoration of memory in the treated animals was associated with a switch in activated microglia from a CD11b+/TNFα+ type to a CD11c+/MHC II+ type with dendritic-like morphology, resulting in a lowering of amyloid load and restoration of cognition. It now appears, however, that these are dendritic cells derived from the bone marrow (121). Based on the previous work of these authors, these cells appear to be capable of expressing antigen, secreting growth factors, and buffering glutamate (106, 107, 122). In contrast to the direct infusion of T cells, Frenkel et al. (123) used a proteosome-based adjuvant plus glatiramer acetate vaccination strategy to presumably increase T cell entry in an AD mouse model. Among animals treated, less amyloid load corresponded to greater numbers of T cells, interferon-γ secreting cells, and innate activated microglia.
Conclusions.
Perfusions of CNS antigen-exposed T cells or T cells from healthy animals lower amyloid load and restore memory in AD mouse models. Although the above studies emphasize the potential therapeutic importance of T cell infusion or modification, these studies do not directly address the role of “native” brain T cells in the immune response to amyloid pathology or its age dependency. Because microarray studies of aging in humans have consistently shown increased expression in genes associated with inflammation in the brain (124, 125) and other studies have shown increased numbers of activated astrocytes and microglia (126), the aging of the brain's immune response to β-amyloid provides one plausible explanation for the strong age dependence of AD risk.
ADDITIONAL IMMUNE-MEDIATED APPROACHES TO THE TREATMENT OF AD
In addition to the earlier mentioned nonsteroidal anti-inflammatory drugs, epidemiological studies have also suggested that a reduction in AD risk is seen in individuals who are receiving statins. These inhibitors of 3-hydroxy-3-methylgutaryl coenzyme A reductase, thought perhaps to be acting through a mechanism related to cholesterol and its effect on membrane structure and Aβ processing, might also have an immune system component by down-regulating MHC II molecules and costimulatory molecules and cytokines that favor Th1 T-cell development, moving T cells toward a Th2 response (126). Further, in AD mouse models Aβ40 and Aβ42 are able to attract bone marrow cells into the CNS, resulting in microglia that can phagocytose β-amyloid (128). These cells could potentially be modified to express various factors including enzymes capable of degrading amyloid and neurotrophic and neuroprotective factors (108).
Although passive and active vaccination approaches that target amyloid have attracted the most attention, there remain issues related to efficacy as well as concerns about potentially serious side effects that include encephalitis and microhemorrhages (128). Recently Obregon et al. (129) reported the use of a dual active vaccination strategy in mice in which active vaccination against Aβ is combined with active vaccination against CD40L, potentially resulting in a reduction in cerebral amyloid angiopathy and microhemorrhages.
Conclusions.
Strategies for the prevention and treatment of AD run the gamut from macromolecular, e.g., cognitive stimulation, to the molecular; most molecular approaches have focused on targets based on the “amyloid cascade hypothesis” (4). These approaches have included
1) inhibiting the β- and γ-secretases, the enzymes responsible for the production of Aβ1-40 and Aβ1-42, which are molecules that have a propensity to aggregate, at first as oligomers, and then as insolubles, e.g., as plaques,
2) enhancing alternative pathways of processing APP, e.g., α-secretase,
3) using drugs that block the aggregation process or promote disaggregation,
4) using strategies meant to increase the clearance of TPs of the APP processing pathway from the brain, including the enhancement of enzymes that degrade Aβ (Aβ1-x where x can vary between 39 to 42) or enhance transport out of brain, and
5) using strategies to protect neurons.
The immune system represents an attractive target for both enhancing clearance of Aβ and providing neuroprotection. However, we are only in the early stages of understanding of the role of the immune system in aging and AD, having created the beginning of an inventory of the responses of some of the elements of the immune system, but still far from a blueprint. To be successful it will be necessary for us to decipher how and when different cells of the brain's immune system work together, how messages travel between and within the cells of this immune network, and how the effects of aging and the elements of AD pathology spread along this complex immune network and are modified by different genotypes. Despite these challenges, it appears likely the immune system will be an important component of any future strategy to treat neurodegenerative disorders.
1 Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297: 353– 356Crossref, Google Scholar
2 Schenk D, Hagen M, Seubert P: Current progress in β-amyloid immunotherapy. Curr Opin Immunol 2004; 16: 599– 606Crossref, Google Scholar
3 Boche D, Nicoll JAR, Weller RO: Immunotherapy for Alzheimer's disease. Curr Opin Neurol 2005; 18: 720– 725Crossref, Google Scholar
4 Cummings JL, Doody R, Clark C: Disease modifying therapies for Alzheimer's disease. Neurology 2007; 69: 1622– 1634Crossref, Google Scholar
5 Blennow K, de Leon MJ, Zetterberg H: Alzheimer's disease. Lancet 2006; 368: 387– 403Crossref, Google Scholar
6 Itagaki S, McGeer PL, Akiyama H: Presence of T-cytotoxic suppressor and leukocyte common antigen positive cells in Alzheimer's disease brain tissue. Neurosci Lett 1988; 91: 259– 264Crossref, Google Scholar
7 Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K: Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J Neuroimmunol 2002; 124: 83– 92Crossref, Google Scholar
8 Town T, Nikolic V, Tan J: The microglial “activation continuum: from innate to adaptive responses. J Neuroinflammation 2005; 2: 24– 33Crossref, Google Scholar
9 Katzman R: Alzheimer's disease. N Engl J Med 1986; 314: 964– 973Crossref, Google Scholar
10 Glenner GG, Wong CW: Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885– 890Crossref, Google Scholar
11 Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82: 4245– 4249, 1985Crossref, Google Scholar
12 Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A: Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 1988; 85: 4051– 4055Crossref, Google Scholar
13 Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad Sci USA 1986; 83: 4913– 4917Crossref, Google Scholar
14 Ihara Y, Nukina N, Miura R, Ogawara M: Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem (Tokyo) 1986; 99: 1807– 1810Google Scholar
15 Kosik KS, Joachim CL, Selkoe DJ: Microtubule-associated protein τ (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad. Sci USA 1986; 83: 4044– 4048Crossref, Google Scholar
16 Findeis MA: The role of amyloid beta peptide 42 in Alzheimer's disease. Pharmacol Ther 2007; 116: 266– 286Crossref, Google Scholar
17 Walsh DM, Selkoe DJ: Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 2004; 44: 181– 193Crossref, Google Scholar
18 Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci 2005; 8: 79– 84Crossref, Google Scholar
19 Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puolivali J, Lesne S, Ashe KH, Muchowski PJ, Mucke L: Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 2007; 282: 23818– 23828Crossref, Google Scholar
20 LaFerla FM, Green KN, Oddo S: Intracellular amyloid-β in Alzheimer's disease. Nat Rev Neurosci 2007; 8: 499– 509Crossref, Google Scholar
21 Wegiel J: Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degeneration. Acta Neuropathol (Berl) 2007; 113: 389– 402Crossref, Google Scholar
22 Haga S, Akai K, Ishii T: Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain: an immunohistochemical study using a novel monoclonal antibody. Acta Neuropathol (Berl) 1989; 77: 569– 575Crossref, Google Scholar
23 McGeer PL, Itagaki S, Tago H, McGeer EG: Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987; 79: 195– 200Crossref, Google Scholar
24 Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D: Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 1989; 24: 173– 182Crossref, Google Scholar
25 Rogers J, Luber-Narod J, Styren SD, Civin WH: Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol Aging 1988; 9: 339– 349Crossref, Google Scholar
26 Kálmán J, Juhász A, Laird G, Dickens P, Járdánházy T, Rimanóczy A, Boncz I, Parry-Jones WL, Janka Z: Serum IL-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease. Acta Neurol Scand 1997; 96: 236– 240Google Scholar
27 Singh VK, Guthikonda P: Circulating cytokines in Alzheimer's disease. J Psychiatr Res 1997; 31: 657– 660Crossref, Google Scholar
28 Alvarez XA, Franco A, Fernandez-Novos L, Cacabelos R: Blood levels of histamine, IL-1β, and TNF-α in patients with mild to moderate Alzheimer disease. Mol Chem Neuropathol 1996; 29: 237– 252Crossref, Google Scholar
29 Licastro F, Parnetti L, Morini MC, Davis LJ, Cucinotta D, Gaiti A, Senin U: Acute phase reactant α1-antichymotrypsin is increased in cerebrospinal fluid and serum of patients with probable Alzheimer disease. Alzheimer Dis Assoc Dis 1995; 9: 112– 118Crossref, Google Scholar
30 Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflammation and Alzheimer's disease. Neurobiol Aging 2000; 21: 383– 421Crossref, Google Scholar
31 Aisen PS: The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease. Lancet Neurol 2002; 1: 279– 284Crossref, Google Scholar
32 McGeer PL, Schulzer M, McGeer EG: Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 1996; 47: 425– 432Crossref, Google Scholar
33 McGeer PL, McGeer EG: NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging 2007; 5: 639– 647Google Scholar
34 Wyss-Coray T: Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12: 1005– 1015Google Scholar
35 Bossú P. Ciaramella A, Moro ML, Bellincampi L, Bernardini S, Federici G, Trequattrini A, Macciardi F, Spoletini I, Di Iulio F, Caltagirone C, Spalletta G: Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease. J Neurol Neurosurg Psychiatry 2007; 78: 807– 811Crossref, Google Scholar
36 Infante J, Llorca J, Mateo I, R Mateo I, Rodríguez-Rodríguez E, Sánchez-Quintana C, Sánchez-Juan P, Fernández-Viadero C, Peña N, Berciano J, Combarros O: Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk. Dement Geriatr Cogn Disord 2007; 23: 215– 218Crossref, Google Scholar
37 Licastro F, Porcellini E, Caruso C, Lio D, Corder EH: Genetic risk profiles for Alzheimer's disease: integration of APOE genotype and variants that up-regulate inflammation. Neurobiol Aging 2007; 28: 1637– 1643Crossref, Google Scholar
38 Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW: Tumor necrosis factor α and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol 2006; 63: 1165– 1169Crossref, Google Scholar
39 Laws SM: TNF polymorphisms in Alzheimer disease and functional implications on CSF β-amyloid levels. Hum Mutat 2005; 26: 29– 35Crossref, Google Scholar
40 Ma SL, Tang NL, Lam LC, Chiu HF: The association between promoter polymorphism of the interleukin-10 gene and Alzheimer's disease. Neurobiol Aging 2005; 26: 1005– 1010Crossref, Google Scholar
41 Arosio B, Trabattoni D, Galimberti L, Bucciarelli P, Fasano F, Calabresi C, Cazzullo CL, Vergani C, Annoni G, Clerici M: Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer's disease. Neurobiol Aging 2004; 25: 1009– 1015Crossref, Google Scholar
42 Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB: In-vivo measurement of activated microglia in dementia. Lancet 2001; 358: 461– 467Crossref, Google Scholar
43 Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, Achten E, Slegers G, Dierckx RA, Korf J: Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195; and single photon emission computed tomography: a pilot study. Eur. Neurol 2003; 50: 39– 47Crossref, Google Scholar
44 Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R: Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991; 30: 572– 580Crossref, Google Scholar
45 Sparks DL, Scheff SW, Liu H, Landers T, Danner F, Coyne CM, Hunsaker JC 3rd: Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients. J Neurol Sci 1996; 138: 97– 104Crossref, Google Scholar
46 Berg L, McKeel DW Jr, Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS, Saunders AM: Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype Arch Neurol 1998; 55: 326– 335Crossref, Google Scholar
47 Bancher C, Jellinger K, Lassmann H, Fischer P, Leblhuber F: Correlations between mental state and quantitative neuropathology in the Vienna Longitudinal Study on Dementia. Eur Arch Psychiatry Clin Neurosci 1996; 246: 137– 146Crossref, Google Scholar
48 Blennow K, Bogdanovic N, Alafuzoff I, Ekman R, Davidsson P: Synaptic pathology in Alzheimer's disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele J Neural Transm Gen Sect 1996; 103: 603– 618Crossref, Google Scholar
49 Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F: Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717] transgenic mice. J Nueroinflammation 2005; 2: 22– 33Crossref, Google Scholar
50 Del Bo R, Aneretti N, Lucca E, De Simoni MG, Forloni G: Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and β-amyloid production in cultures. Neurosci Lett 1995; 188: 70– 74Crossref, Google Scholar
51 Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, Vitek MP, Gajdusek DC: Interleukin 1 regulates synthesis of amyloid β-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci USA 1989; 86: 7606– 7610Crossref, Google Scholar
52 Lahiri DK, Nall C: Promoter activity of the gene encoding the β-amyloid precursor protein is uprregulated by growth factors, phorbol ester retinoic acid and IL-1. Mol Brain Res 1995; 32: 233– 240Crossref, Google Scholar
53 Ringheim GE, Szczepanik AM, Petko W, Burgher KL, Zhu SZ, Chao CC: Enhancement of β-amyloid precursor protein transcription and expression by the soluble IL-6 receptor/IL-6 complex. Mol Brain Res 1998; 55: 35– 44Crossref, Google Scholar
54 Blurton-Jones M, Laferla FM: Pathways by which Aβ facilitates tau pathology. Curr Alzheimer Res 2006; 3: 437– 448Crossref, Google Scholar
55 Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A: Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988; 23: 138– 144Crossref, Google Scholar
56 Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L: Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 1988; 38: 1682– 1687Crossref, Google Scholar
57 Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P, Yen SH, Aronson MK: Identification of normal and pathologic aging in prospectively studied nondemented elderly humans. Neurobiol Aging 1992; 13: 179– 189Crossref, Google Scholar
58 Tronosco CJ, Martin LJ, Dal Forno G, Kawas CH: Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol Aging 1996; 17: 365– 371Crossref, Google Scholar
59 Schmitt FA Davis DG, Wekstein DR, Smith CD, Ashford JW, Markesbery WR: “Preclinical” AD revisited: neuropathology of cognitively normal older adults. Neurology. 2000; 55: 370– 376Crossref, Google Scholar
60 Price JL, Morris JC: Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol. 1999; 45: 358– 368Crossref, Google Scholar
61 Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS: Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006; 66: 1837– 1844Crossref, Google Scholar
62 Lue LF, Brachova L, Civin WH, Rogers J: Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 1996; 55: 1083– 1088Crossref, Google Scholar
63 Vehmas AK, Kawas CH, Stewart WF, Troncoso JC: Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 2003; 24: 321– 331Crossref, Google Scholar
64 Arends YM, Duyckaerts C, Rozemuller JM, Eikelenboom P, Hauw J-J: Microglia, amyloid and dementia in Alzheimer's disease: a correlative study. Neurobiol Aging 2000; 21: 39– 47Google Scholar
65 Sasaki A, Yamaguchi H, Ogawa A, Sugihara S, Nakazato Y: Microglial activation in early stages of amyloid beta protein deposition. Acta Neuropathol 1997; 94: 316– 322Crossref, Google Scholar
66 Wirths O, Breyhan H, Marcello A, Cotel MC, Brück W, Bayer TA: Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging (in press)Google Scholar
67 Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K: Screening of innate immune receptors in neurodegenerative diseases: A similar pattern. Neurobiol Aging (in press).Google Scholar
68 Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC: [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67 446– 452, 2006Crossref, Google Scholar
69 Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Långström B, Nordberg A: Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 2006; 129: 2856– 2866Crossref, Google Scholar
70 Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B: Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004; 55: 306– 319Crossref, Google Scholar
71 Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, Lavretsky H, Burggren AC, Cole GM, Vinters HV, Thompson PM, Huang SC, Satyamurthy N, Phelps ME, Barrio JR: PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006; 355: 2652– 2663Crossref, Google Scholar
72 Pike KE, Savage G, Villemagne VL, Ng S, Moss SA, Maruff P, Mathis CA, Klunk WE, Masters CL, Rowe CC: β-Amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain 2007; 130: 2837– 2844Crossref, Google Scholar
73 Braak H, Braak E: Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 1991; 82: 239– 259Crossref, Google Scholar
74 Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J: Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci USA 2004; 101: 284– 289Crossref, Google Scholar
75 Bookheimer SY: Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med 2000; 343: 450– 456Crossref, Google Scholar
76 Filbey FM, Slack KJ, Sunderland TP, Cohen RM: Functional magnetic resonance imaging and magnetoencephalography: differences associated with APOEε4 in young healthy adults. Neuroreport 2006; 17: 1585– 1590Crossref, Google Scholar
77 Cohen RM, Carson RE, Filbey F, Szczepanik J, Sunderland T: Age and APOE-ε4 genotype influence the effect of physostigmine infusion on the in-vivo distribution volume of the muscarinic-2-receptor dependent tracer [18F]FP-TZTP. Synapse 2006; 60: 86– 92Crossref, Google Scholar
78 Fleisher AS, Houston WS, Eyler LT, Frye S, Jenkins C, Thal LJ, Bondi MW: Identification of Alzheimer disease risk by functional magnetic resonance imaging. Arch Neurol 2005; 62: 1881– 1888Crossref, Google Scholar
79 Bondi MW, Houston WS, Eyler LT, Brown GG: fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology. 2005; 64: 501– 508Crossref, Google Scholar
80 Scarmeas N, Habeck CG, Hilton J, Anderson KE, Flynn J, Park A, Stern Y: APOE related alterations in cerebral activation even at college age. J Neurol Neurosurg Psychiatry 2005; 76: 1440– 1444Crossref, Google Scholar
81 Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR: Linguistic ability in early life and cognitive function and Alzheimer's disease in late life: findings from the Nun Study. JAMA 1996; 275: 528– 532Crossref, Google Scholar
82 Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312– 318Crossref, Google Scholar
83 Monsonego A, Weiner HL: Immunotherapeutic approaches to Alzheimer's disease. Science 2003; 302: 834– 838Crossref, Google Scholar
84 Pasinetti GM: Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: the role of the complement system. Neurobiol Aging 1996; 17: 707– 716Crossref, Google Scholar
85 Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM: RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 1996; 382: 685– 691Crossref, Google Scholar
86 Coraci IS: CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to β-amyloid fibrils. Am J Pathol 2002; 160: 101– 112Crossref, Google Scholar
87 Togo T, Akiyama H, Kondo H, Ikeda K, Kato M, Isaki E, Kosaka K: Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases. Brain Res 2000; 885: 117– 121Crossref, Google Scholar
88 Calingasan NY, Erdely HA, Altar CA: Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol Aging 2002; 23: 31– 39Crossref, Google Scholar
89 Mrak RE, Griffin WS: Interleukin-1, neuroinflammation and Alzheimer's disease. Neurobiol Aging 2001; 22: 903– 908Crossref, Google Scholar
90 Vandenabeele P, Fiers W: Is amyloidogenesis during Alzheimer's disease due to an IL-1/IL-6 mediated ‘acute phase’ response I the brain? Immunol Today 1991; 12: 217– 219Crossref, Google Scholar
91 Ait-Ghezala G, Mathura VS, Laporte V, Quadros A, Paris D, Patel N, Volmar CH, Kolippakkam D, Crawford F, Mullan M: Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease. Brain Res Mol Brain Res 2005; 140: 73– 85Crossref, Google Scholar
92 Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ: Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci 2002; 5: 1288– 1293Crossref, Google Scholar
93 Holtzman DM: Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2000; 97: 2892– 2897Crossref, Google Scholar
94 Potter H, Wefes IM, Nilsson LN: The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation. Neurobiol Aging 2001; 22: 923– 930Crossref, Google Scholar
95 Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, Masliah E: Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci USA 2002; 99: 10837– 10842Crossref, Google Scholar
96 Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ: Insulin-degrading enzyme regulates extracellular levels of amyloid β-protein by degradation. J Biol Chem 1998; 273: 32730– 32738Crossref, Google Scholar
97 Qiu WQ, Ye Z, Khologenko D, Seubert P, Selkoe DJ: Degradation of amyloid β-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J Biol Chem 1997; 272: 6641– 6646Crossref, Google Scholar
98 Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O'Hare E, Esler WP, Maggio JE, Mantyh PW: Fibrillar β-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 1998; 18: 2161– 2173Crossref, Google Scholar
99 Koenigsknecht J, Landreth G: Microglial phagocytosis of fibrillar β-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 2004; 24: 9838– 9846Crossref, Google Scholar
100 Paresce DM, Ghosh RN, Maxfield FR: Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 1996; 17: 553– 565Crossref, Google Scholar
101 El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD: Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 1996; 382: 716– 719Crossref, Google Scholar
102 El Khoury J, Hickman SE, Thomas CA, Loike JD, Silverstein SC: Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease. Neurobiol Aging 1998; 19: 81– 84Crossref, Google Scholar
103 Herber DL, Roth LM, Wilson D, Wilson N, Mason JE, Morgan D, Gordon MN: Time-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice. Exp Neurol 2004; 190: 245– 255Crossref, Google Scholar
104 Wilcock DM, Muniredddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D: Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol Dis 2004; 15: 11– 20Crossref, Google Scholar
105 Wyss-Coray T, Mucke L: Inflammation in neurodegenerative disease—a double-edged sword. Neuron 2002; 35: 419– 432Crossref, Google Scholar
106 Schwartz M, Moalem G, Leibowitz-Amit R, Cohen IR: Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci 1999; 22: 295– 299Crossref, Google Scholar
107 Schwartz M, Kipnis J: Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases. J Neurol Sci 2005; 233: 163– 166Crossref, Google Scholar
108 Simard AR, Soulet D, Gowing G, Julien JP, Rivest S: Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 2006; 49: 489– 502Crossref, Google Scholar
109 Town T, Nikolic V, Tan J: The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation. 2005; 2: 24Crossref, Google Scholar
110 Streit WJ: Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev 2005; 48: 234– 239Crossref, Google Scholar
111 Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M: Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protective. Mol Cell Neurosci 2005; 29: 381– 393Crossref, Google Scholar
112 Streit WJ: Microglia and Alzheimer's disease pathogenesis. J Neurosci Res 2004; 77: 1– 8Crossref, Google Scholar
113 Streit WJ, Sammons NW, Kuhns AJ, Sparks DL: Dystrophic microglia in the aging human brain. Glia 2004; 45: 208– 212Crossref, Google Scholar
114 Irani DN, Griffin DE: Regulation of lymphocyte homing into the brain during viral encephalitis at various stages of infection. J Immunol 1996; 156: 3850– 3857Google Scholar
115 Yeager MP, DeLeo JA, Hoopes PJ, Hartov A, Hildebrandt L, Hickey WF: Trauma and inflammation modulate lymphocyte localization in vivo: quantitation of tissue entry and retention using indium-111-labeled lymphocytes. Crit Care Med 2000; 28: 1477– 1482Crossref, Google Scholar
116 Owens T, Tran E, Hassan-Zahraee M, Krakowski M: Immune cell entry to the CNS—a focus for immunoregulation of EAE. Res Immunol 1998; 149: 781– 789Crossref, Google Scholar
117 Carro E, Trejo JL, Spuch C, Bohl D, Heard JM, Torres-Aleman I: Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: new cues into the human disease? Neurobiol Aging 2006; 27: 1618– 1631Crossref, Google Scholar
118 Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P, Rosengren LE, Olsson T, Gage FH, Eriksson PS: IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci 2003; 24: 23– 40Crossref, Google Scholar
119 Ethell DW, Shippy D, Cao C, Cracchiolo JR, Runfeldt M, Blake B, Arendash GW: Aβ-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice. Neurobiol Dis 2006; 23: 351– 361Crossref, Google Scholar
120 Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, Schwartz M: Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci USA. 2006; 103: 11784– 11789Crossref, Google Scholar
121 Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M: Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur J Neurosci 2007; 26: 413– 416Crossref, Google Scholar
122 Shaked I, Tchoresh D, Gersner R, Meiri G, Mordechai S, Xiao X, Hart RP, Schwartz M: Protective autoimmunity: interferon-γ enables microglia to remove glutamate without evoking inflammatory mediators. J Neurochem 2005; 92: 997– 1009Crossref, Google Scholar
123 Frenkel D, Maron R, Burt DS, Weiner HL: Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest. 2005; 115: 2423– 2433Crossref, Google Scholar
124 Blalock EM, Chen KC, Stromberg AJ, Norris CM, Kadish I, Kraner SD, Porter NM, Landfield PW: Harnessing the power of gene microarrays for the study of brain aging and Alzheimer's disease: statistical reliability and functional correlation. Ageing Res Rev 2005; 4: 481– 512Crossref, Google Scholar
125 Finch CE: Neurons, glia, and plasticity in normal brain aging. Neurobiol Aging 2003; 24 ( suppl 1): S123– S127Crossref, Google Scholar
126 Youssef S, Stüve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS: The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002; 420: 78– 84Crossref, Google Scholar
127 Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA: Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 2008; 14: 681– 687Crossref, Google Scholar
128 Geylis V, Steinitz M: Immunotherapy of Alzheimer's disease (AD): from murine models to anti-amyloid (Aβ) human monoclonal antibodies. Autoimmun Rev 2006; 5: 33– 39Crossref, Google Scholar
129 Obregon D, Hou H, Bai Y, Nikolic WV, Mori T, Luo D, Zeng J, Ehrhart J, Fernandez F, Morgan D, Giunta B, Town T, Tan J: CD40L disruption enhances Aβ vaccine-mediated reduction of cerebral amyloidosis while minimizing cerebral amyloid angiopathy and inflammation. Neurobiol Dis 2008; 29: 336– 353Crossref, Google Scholar
