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A Perspective on Inflammation in Alzheimer’s Disease

JOSEPH ROGERSa AND YONG SHEN

Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, Arizona 85351, USA

ABSTRACT: Although there have been hundreds of recent papers that doc-ument a role for innate inflammatory responses in Alzheimer’s disease(AD), several global issues and organizational points are still worth em-phasizing. These include etiologic versus pathogenic roles for AD inflam-mation, the potency of AD inflammation, the sources of AD inflammation,and the highly interactive nature of AD inflammatory responses.

KEYWORDS: Alzheimer’s disease; Inflammation; Cytokines; Comple-ment; Acute-phase proteins; Microglia

There are now several thousand basic science studies and some two dozenclinical studies1 suggesting that inflammation may play a role in the develop-ment and progression of Alzheimer’s disease (AD). Nonetheless, there stillremain important issues and consistent misunderstandings about this re-search area, even among its practitioners, that require discussion. The follow-ing is a brief summary of some of these points gleaned from rebuttals torejected manuscripts and grant proposals over the last two decades.

Inflammation is unlikely to be an etiology of AD. Inflammation is almostnever the root cause or etiology of any peripheral disorder, and this is proba-bly equally true for AD. Rather, as the phrase inflammatory response implies,inflammation is typically a secondary reaction to some other, more primarypathogen or process.

To say that inflammation is a secondary reaction in AD is not to say that itis unimportant. If a patient is hit on the head with a board, the etiology of hisproblem is the blow to the head. What is more likely to kill him, however, isthe secondary inflammatory reaction. Similarly, the ingestion of an innocu-ous scallop can, in some patients, engender a lethal, secondary inflammatoryresponse. Hundreds of precedents can, in fact, be given in which secondary

aAddress for correspondence: Joseph Rogers, Ph.D., Sun Health Research Institute, P.O. Box1278, Sun City, Arizona 85372. Voice: 623- 876-5466; fax: 623-876-5461.

e-mail: jrogers@mail.sunhealth.org

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inflammatory reactions come to be as pathophysiologically relevant as theprimary pathogen that gave rise to them. AD is such a disorder.

Inflammation is one of the mechanisms that damages the brain in AD.The pathophysiologic relevance of inflammation to AD neurodegenerationhas received increased attention on several grounds. First, many of the in-flammatory mechanisms that have been uncovered in the AD brain1 areovertly cytotoxic in the periphery;2 it would therefore be surprising if theywere not also cytotoxic in the brain, an organ that is exquisitely sensitive toinflammation. Second, upregulated inflammatory mechanisms colocalize inthe AD brain with those regions that exhibit high levels of AD pathology(e.g., frontal neocortex, limbic cortex) and are absent or minimal in brain re-gions with low AD pathologic susceptibility (e.g., cerebellum).1 Third, at themicroscopic level, inflammatory mediators are most highly expressed in thevicinity of amyloid β peptide (Aβ) deposits and neurofibrillary tangles, clas-sical AD hallmarks where neurodegeneration is known to occur.1 Fourth, pa-tients without history of dementia but who nonetheless exhibit sufficientlimbic Aβ and tangles at autopsy to otherwise qualify for the diagnosis of ADshow only modest elevations of inflammatory markers, slightly greater thantypical nondemented elderly patients but dramatically less than AD patients.3

Fifth, direct evidence of inflammatory toxicity can be observed in the ADbrain. For example, complement fixation and lysis of neurites can be demon-strated ultrastructurally.4 Sixth, nearly two dozen clinical studies have strong-ly suggested that conventional anti-inflammatory drugs may delay the onsetor slow the progression of AD. Although many of these studies have been ret-rospective,5 with all the caveats that obtain in such work, a few—particularlyrecent studies at Johns Hopkins University, Duke University, and Sun HealthResearch Institute—have been more directly prospective, including a double-blind, placebo-controlled trial of a conventional nonsteroidal antiinflamma-tory drug (NSAID) in 28 AD patients.6

AD inflammation is chronic but weak. As noted above, the central ner-vous system is extremely sensitive to inflammation. Were the inflammatoryreaction in AD as potent as that in, say, glomerular nephritis, AD would prob-ably be a terminal disorder in a matter of days, not years. Moreover, many ofthe mechanisms that regulate inflammation in the periphery are dramaticallyincreased in the AD brain1—another sign of the pathophysiologic relevanceof AD inflammation. Thus, in keeping with a slowly progressing disease, ADinflammation must cumulate microlocalized damage over many years.

There are obvious stimuli for chronic AD inflammation. Peripheral inflam-matory reactions almost universally occur in response to local tissue damageand the deposition of abnormal or inert materials (e.g., bacteria, viruses, deadcells, dirt). Neurodegeneration and profuse deposition of abnormal, inert ma-terials—Aβ aggregates and neurofibrillary tangles—occur in the AD brain.Numerous basic science studies have shown that these pathologic entitiesstimulate multiple mechanisms of inflammation.1 For example, aggregatedAβ7 and aggregated tau (Shen et al., in preparation) activate complement.

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Because Aβ deposits and tangles are present from preclinical to terminalstages of the disorder, they readily provide an initiating and sustaining sourcefor chronic inflammation. This is, in fact, why virtually all AD inflammatorymediators tend to be microlocalized at sites of Aβ deposition and neurofibril-lary tangle formation.

AD inflammation does not appear to involve lymphocytes or autoantibod-ies. Unequivocal evidence of lymphocyte or autoantibody involvement inAD has been lacking. Although absence of proof does not constitute proof ofabsence, significant efforts have been made to find differential numbers ortypes of T-cells, differential expression of antibodies, and any presence at allof B-cells in the AD brain. These studies have generally given mixed or, moreoften, negative results. Thus, AD inflammation does not appear to reflect thetype of humoral, antibody-mediated response that has largely dominatedclassical neuroimmunologic research for the last few decades, nor is AD in-flammation likely to yield to the treatment approaches suggested by classicalneuroimmunologists (e.g., steroid antiinflammatory drugs).

AD inflammation does involve endogenous cell-mediated responses, par-ticularly complement, cytokine, and acute-phase responses. A virtual text-book of inflammatory mediators has been shown to be upregulated in the ADbrain.1 Although the initial source for these molecules remains unknown, andthey could come from the periphery through a damaged blood-brain barrier,it is clear that once AD has reached full clinical expression, endogenous braincells are fully capable of sustaining the production of complement proteins,cytokines, and many acute-phase reactants. Indeed, at least one study has es-timated that the capacity of the AD brain to generate complement proteinsmay be greater than that of the liver.8

Schemas of AD inflammation emphasize the highly interactive nature ofits individual mechanisms. As in the periphery, AD inflammation is made upof a complex set of interactive, feedforward and feedback mechanisms.1

Through complement receptors expressed by microglia, for example, com-plement activation fragments can induce cytokines. Cytokines, in turn, caninduce acute-phase proteins, chemokines, free radicals, additional cytokines,and more complement. Some of the classical elements of peripheral inflam-mation (e.g., macrophage scavenger receptors, α1-antichymotrypsin, α2-macroglobin, serum amyloid P, C1q, C3) turn out to have binding affinitiesfor Aβ. S100B may stimulate neurite outgrowth. IL-1β may stimulate APP.Aβ, in a dose-dependent manner, stimulates cytokine, chemokine, and com-plement production by cultured AD microglia. In the end, the nearly bewil-dering interactions among the many inflammatory mediators that have beendetected in the AD brain, both among themselves and with classical AD pa-thology, make it difficult to assert that any one mediator or set of mediatorsis more important or more primary than any other. To have one is to havethem all; they are all worthy of study.

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ACKNOWLEDGMENTS

Preparation of this manuscript was supported by NIA AGO7367, grantsfrom the Alzheimer’s Association, and a grant from the State of ArizonaAlzheimer’s Disease Research Center.

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