inflammation and alzheimer's disease pathogenesis

ELSEVIER PII S0197-4580(96)00115-7

Neurobiology of Aging, Vol. 17, No. 5, pp. 681-686, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved

0197-4580/96 $15.00 + .00

Inflammation and Alzheimer's Disease Pathogenesis

J O S E P H R O G E R S , 1 S C O T T W E B S T E R , L I H - F E N L U E , L I B U S E B R A C H O V A , W. H A R O L D C I V I N , M A R K E M M E R L I N G , B R E N D A S H I V E R S , D O U G L A S W A L K E R A N D P A T R I C K M C G E E R

Sun Health Research Institute, 10515 West Santa Fe Drive, P.O. Box 1278, Sun City, AZ 85372 Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Road, Ann Arbor, MI 48105

University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada

R e c e i v e d 14 O c t o b e r 1995; R e v i s e d 1 Apr i l 1996; A c c e p t e d 8 M a y 1996

ROGERS, J., S. WEBSTER. L.-F. LUE, L. BRACHOVA, W. H. CIVIN, M. EMMERLING, B. SHIVERS, D. WALKER AND P. MCGEER. Inflammation and Alzheimer's disease pathogenesis. NEUROBIOL AGING 17(5) 681~586, 1996.--Appreciation of the role that inflammatory mediators play in Alzheimer's disease (AD) pathogenesis continues to be hampered by two related miscon- ceptions. The first is that to be pathogenically significant a neurodegenerative mechanism must be primary. The second is that inflammation merely occurs to clear the detritis of already existant pathology. The present review addresses these issues by showing that 1) inflammatory molecules and mechanisms are uniquely present or significantly elevated in the AD brain, 2) inflammation may be a necessary component of AD pathogenesis, 3) inflammatio n may be sufficient to cause AD neurodegeneration, and 4) retrospective and direct clinical trials suggest a therapeutic benefit of conventional antiinflammatory medications in slowing the progress or even delaying the onset of AD.

Alzheimer' s disease Dementia Neurodegeneration Inflammation Complement Cytokines

SINCE initiating our studies of inflammation and Alzheimer 's disease (AD) more than a decade ago (81), it has been gratifying to see the explosive growth of this field as, one by one, numerous molecules and mechanisms of peripheral inflammatory responses have been identified in the AD brain. This research began with the seminal experiments of Ishii and Haga (40,43), who first noted the appearance of immune-related elements in electron micrographs of AD cortical samples, and it continues today in studies of cytokines, complement, complement defense proteins, acute phase reactants, microglial activation, scavenger attack, and other indices of inflammation.

To those familiar with the inherent destructiveness of peripheral inflammatory molecules and mechanisms, their identification in AD brain (and typical absence or paucity in similar control samples) is presumptive evidence of a significant role in AD pathogenesis. To others, however, a central question remains: are inflammatory processes present in AD brain to remove the detritus of already existing damage or are these processes, in and of them- selves, a significant cause of damage? It is the thesis of this review that both propositions are true. That is, inflammation probably arises in the AD brain as a response to already existing damage, just as it most often does in the periphery. However, as in many common peripheral inflammatory disorders (e.g., asthma, arthritis), the AD brain provides numerous opportunities for chronic inflammation to do more damage than the primary pathologic events that invoked it. This can be seen at several levels of proof,

from the indirect inferences of basic research to direct clinical tests.

INFLAMMATORY MOLECULES AND MECHANISMS ARE UNIQUELY PRESENT OR SIGNIFICANTLY ELEVATED IN THE AD BRAIN

Table 1 lists many of the different inflammation-related molecules that have been identified in the AD brain. They are typically either uniquely present or significantly elevated in comparison to similar samples from nondemented elderly (ND) patients.

The particular modes of action of these substances and how they may interact with the pathophysiology of AD are covered in detail in the other chapters of this volume. What is important to note here is that many of these molecules are well established as critical components of the multifaceted inflammatory assault that can be mounted against cells, both damaged and healthy. For example, the classical complement cascade, the full range of which has been amply documented in AD brain (11,22,23,41,42,44,49, 65,78,93), mediates attack by multiple mechanisms: it provides signals for scavenger activation and migration (the anaphylotoxins C4a, C3a, and CSa); it opsonizes targets (C3b, CR3, CR4), sin- gling them out for destruction; and it directly lyses cells (C5b-9) by opening holes in their membranes, permitting massive Ca 2+ influx (55). Microglia in the AD brain begin to express markers of activation (e.g., MHCII) (45,57,62,69,80,88), as well as comple-

J To whom requests for reprints should be addressed. Dr. Joseph Rogers, Sun Health Research Institute, P.O. Box 1278, Sun City, AZ 85372.

681

682 ROGERS ET AL.

TABLE 1

MARKERS OF INFLAMMATION IN THE ALZHEIMER'S BRAIN

MHC I (67) MHC II

HLA-DR (23,45,57,62,67,69,80,81,88)

HLA-DP (57) HLA-DQ (57)

Cytokines IL- le~ (37) IL- 113 (15,16,99) IL-6 (8,85,87,99) TNF (27)

Cytnkine Receptors IL-2R (45,57)

Leucocyte Common Antigen CD45 (67,82)

Leucocyte Adhesion Molecules ICAM- 1 (23,26,30,31,92)

Fc Receptors FcyRl (67)

Acute Phase Reactants cx- 1 -antichymotrypsin (1,2,34,83) ~-2-macroglobulin (8,87,91,99) Serum Amyloid P (19,21,51,53,89) ~- 1-antitrypsin (34) C-reactive protein (46,99)

Classical Complement Proteins Clq ( 11,22-25,41,42,66,67,78) C4 (22,25,41,42)

C4d (59,66,67,78) C3 (22~23,25,41,42) C3b (25) C3c (22,25) C3d (22,25,66,67) C7 (67) C9 (67) C5b-9 (MAC) (44,66.67,78,96)

Classical Complement mRNAs Clq (49,93) C4 (49,93) C3 (93)

Complement Defense Proteins MIRL (74) Clusterin (APOJ. SP40,40) (18,65,70) Vitronectin (4) C4BP (51,90) C 1-1NH (22,94)

Complement Receptors CR3 (5,23,26,67) CR4 (5,23)

ment and cytokine receptors (e.g., CR3, CR4, IL-2R) (5,23,26,57, 72,82). Toxic cytokines (e.g., TNF) are upregulated (8,27,37,86, 87,99).

Other inflammation-related molecules present in the AD brain demonstrate that physiologically relevant attack is ongoing there. For example, when peripheral tissue undergoes significant inflammatory attack, cells in the area begin to express complement defense proteins such as the membrane inhibitor of reactive lysis (CD59), C4 binding protein (C4BP), CI inhibitor (CIINH), and apolipoprotein J (ApoJ). These proteins are also upregulated (4, 18,20,51,64,66,70,74,90,94) in AD brain areas associated with neurodegeneration (e.g., plaques and tangles), which in turn, colocalize with markers of inflammatory attack.

Still other inflammation-related proteins have been demon- strated to interact uniquely with AD pathology and to exacerbate it. For example, several of the acute phase reactants (ACT, SAP, C I q) have been reported to alter the rate of aggregation of amyloid [3 peptide (A[3) into its neurotoxic, cross (3-pleated configuration (29,38,60,89,95,97). C 1 q, by far the most potent of these A[3 binding proteins in accelerating A[3 fibrillogenesis (98), is the first component of the classical complement pathway. Its binding to A[3 not only foments aggregation but also fully activates the classical pathway (48,78), leading to formation of the membrane attack complex (MAC, C5b-9). Finally, in addition to their traditional roles as paracrine and autocrine messengers of inflammatory processes, some of the cytokines (IL-I[3) may influence A[3 precursor protein expression and/or A[3 metabolism (15,28,33,36,37).

The wide range of inflammatory mediators discovered in AD brain has been confirmed in numerous publications (Table 1) so that there is little controversy anymore as to their presence. An important exception may be C5b-9, brain immunoreactivity for which has recently been suggested to be an artifact of crossreac- tivity with some other protein (24). To address this issue, we have

gathered together evidence from multiple laboratories using multiple techniques with multiple antibodies and cDNA probes (Web- ster et al., in preparation). We find that immunoreactive C5b-9 is present at the light microscopic level in AD but not ND neocortex using three different anti-C5b-9 antibodies. At the ultrastmctural level C5b-9 immunoreactivity colocalizes with cell membranes, as it should, and cells demonstrating such immunoreactivity show responses characteristic of C5b-9 fixation (see below), mRNAs for complement components that form the C5b-9 complex are detected in AD brain samples. Western blot analyses of AD homog- enates reveal anti-C5b-9 immunoreactive bands with the same electrophoretic mobility as C5b-9 generated in vitro. Given these data, it is most parsimonious to believe that the C5b-9 detected in AD brain is true C5b-9.

In summary, the first level of proof that inflammation is a cause of the neurodegeneration underlying AD dementia is the significant elevation of inflammatory proteins in AD compared to ND brain. Some of these upregulated proteins have cellular attack as their primary role; others interact uniquely with classical AD pathology to enhance toxicity; still others signal that physiologically relevant attack is ongoing.

INFLAMMATION MAY BE A NECESSARY COMPONENT OF AD PATHOGENESIS

Subsets of patients, anecdotally or formally documented not to have exhibited symptoms of dementia in life, have been observed at autopsy to exhibit profuse AD pathology (9,10,52). Similarly, AD patients most often have numerous cerebellar A[3 deposits with diffuse morphology, yet cerebellar symptomology and neurodegeneration are atypical of the disorder (11,59,61). Such find- ings have led to the concept that A[3 may be necessary but is not sufficient to cause AD neurodegeneration and dementia. If so,

INFLAMMATION AND ALZHEIMER'S DISEASE 683

what other elements could make A[3 sufficient? One of several possible answers is that inflammation is necessary.

Our laboratory's analysis of inflammation in the AD cerebellum, for example, shows that complement activation fails in the context of the amorphous A[3 deposits there (11,59). By immuno- histochemistry, early-stage complement components are present, but the crucial late-stage components that actually lyse cells (C5b- 9) are weakly detected if at all (59). Western blots to quantify these results demonstrate that even the early-stage complement components are in scant supply in the AD cerebellum, with concentrations barely above background and some sevenfold less than in frontal cortex samples from the same patients (1 l).

We have also evaluated elderly patients who come to autopsy without history of dementia, but who, nonetheless, exhibit sufficient entorhinal cortex plaque and tangle pathology to otherwise qualify for the diagnosis of AD (10). As in other studies, these patients show no evidence of synapse loss and, in fact, have significantly greater brain weights than normal elderly controls (52). Analyses of inflammatory elements such as the MAC in these high pathology nondemented patients reveal levels more comparable to those of ND patients and dramatically less than those of AD patients (10).

Inflammatory mechanisms may also render significant neurotoxicity to otherwise innocuous concentrations of A[3. For example, the typical threshold for A[3 neurotoxicity in culture is generally held to be around 25-100 ~M (cf. 54,63,76,100). These studies, however, have been conducted under conditions where A[3-mediated complement activation could not occur. When such activation is permitted, nM A[3 concentrations prompt significant neurotoxicity (85).

In summary, the diffuse AI3 deposits that often occur in AD cerebellum and the profuse tangles and compacted A[3 deposits that sometimes occur in ND patients suggest that neither of these classical AD hallmarks are sufficient to cause neurodegeneration or clinical signs unless full-blown inflammatory reactions are also present.

INFLAMMATION MAY BE SUFFICIENT TO CAUSE AD NEURODEGENERATION

In addition to their potential necessity for AD pathogenesis, it is also likely that inflammatory reactions are sufficient on their own to cause significant damage to the AD brain. Markers of inflammatory attack colocalize precisely with virtually all forms of AD neurodegeneration, including neurofibrillary tangle containing neurons, neuropil threads, and the dystrophic neurites coursing through A[3 deposits (1-4,18,19,22,23,25,30,31,41,49,50,65- 67,70,71,74,78,83,91,92). Electron micrographs of complement immunoreactivity in the vicinity of A[3 deposits are particularly informative in this regard (44,96). Here, axons decorated with complement are observed. That these axons are under active and effective complement attack can be seen from their characteristic blebbing and endocytosis of the complement proteins, a tactic employed by peripheral cells under inflammatory conditions. Note that the fact that these cell processes are capable of hlebbing and endocytosis proves that they are not already existing AD detritus. Rather, they are the axons of living cells under an active complement attack.

Our culture studies (85) may also be relevant to the proposition that AD inflammation is sufficient to damage or destroy neurons. In this work, the neurotoxic effect of A[3 on hippocampal neurons was tested in the presence of vehicle, dilute normal human serum, or dilute human serum depleted of C3, one of the pivotal complement components. None of the latter three conditions alone pro-

duced detectable toxicity, nor did nM concentrations of A[3 with vehicle or C3 depleted serum. However, significant culture toxicity was observed at nM A[3 levels when dilute normal serum was available. That this effect is attributable to A[3-mediated complement attack is shown by the C3 depletion control, because such serum contains all the other normal elements of serum but C3, without which the complement cascade cannot go to completion.

In summary, there is ample peripheral and CNS precedent for the destructive power of inflammatory reactions. It should there- fore come as no surprise that direct inflammatory attack and lysis of neurons can be observed in the AD brain (96) and in culture models of AD pathophysiology (85).

RETROSPECTIVE AND DIRECT CLINICAL TRIALS SUGGEST A THERAPEUTIC BENEFIT OF CONVENTIONAL ANTIINFLAMMATORY

MEDICATIONS IN SLOWING THE PROGRESS OR EVEN DELAYING THE ONSET OF AD

At least 14 such reports have now been published (6,12- 14,17,35,47,56,58,68,73,75,77,79). Of the retrospective studies, two may be especially noteworthy. In one of them (12), prior history of antiinflammatory drug use was associated with de- creased susceptibility to or delayed onset of AD in a large cohort of elderly identical twins. In the other report (77), disease progression was tracked in some 200 AD patients, a subset of whom were taking nonsteroidal antiinflammatory drugs (NSAIDs). The latter group exhibited significantly slower disease progression.

We have also conducted a very small but direct clinical trial with the NSAID indomethacin (79). Indomethacin was chosen because it has been documented readily to cross the blood-brain harrier. In this double-blind study 28 probable AD patients were randomly assigned to drug or placebo for 6 months. By the end of the trial placebo patients had deteriorated an average 11% on cog- nitive status tests. Under these same conditions indomethacin patients improved nearly 2% on average.

The Alzheimer's Disease Clinical Trials Consortium of the National Institute on Aging is now conducting a multicenter trial of an antiinflammatory as a treatment for AD. Although the choice of a corticosteroid antiinflammatory for this research leaves, in our view, much to be desired, we must, nonetheless, retain an open mind as to the potential outcome. Corticosteroids have been widely reported to be toxic to hippocampal neurons (84), cause substantial adverse reactions when given long term even in low doses (39), and precipitated significant adverse behavioral changes in a pilot trial with four AD patients (79), On these grounds alone, the fail- ure of a corticosteroid trial for AD should not be taken as a reason to dismiss antiinflammatory approaches to treatment of the disorder. Hopefully, the Consortium will consider an NSAID trial re- gardless of the outcome with corticosteroids. Other than through the Consortium, it is doubtful that a large-scale trial of any cur- rently available NSAID will be mounted because these agents typically were developed many years ago and have little or no patent life.

CONCLUSIONS

Inflammation is unlikely to be an etiologic cause of AD nor is it likely to be the only pathogenic mechanism in AD. There is now, however, substantial evidence that inflammation is an important contributor to AD pathology and the neurodegeneration that surely underlies AD dementia. Several different mechanisms have been elucidated, from traditional inflammatory attack to unique inter- actions with AD pathology. These mechanisms often have prop- erties of a vicious cycle. For example, C l q accelerates the aggre-

684 R O G E R S ET AL.

gat ion o f A[3 (95,97,98) and the more aggrega ted A[3 becomes the better it act ivates C l q (48). A[3 s t imula tes cytokine product ion (7,32), wh ich may, in turn, s t imula te A[3 precursor protein product ion (15,28,33,36). As in the periphery, these loops are l ikely to be e m b e d d e d wi th in a larger v ic ious cycle where in t issue degen- erat ion f rom other, more pr imary sources (e.g., tangle format ion, A[3 depos i t ion , head t r auma , ag ing) s t imula tes i n f l ammat ion , which causes further degenera t ion, wh ich causes fur ther inf lam- mat ion, and so on. C u m u l a t e d over m a n y years, it is difficult to imag ine that these processes would not substant ia l ly damage the

AD brain. Thus , there is ample rationale for an t i in f lammatory drug trials in AD, and good reason to hope that they will prove effective.

ACKNOWLEDGEMENTS

Our research has been supported by the National Institute on Aging. the Alzbeimer's Association, the French Foundation, The Helen Bader Foun- dation, the Medical Research Council of Canada, and private contributions from the people of Vancouver, Canada, and Sun City and Sun City West, AZ.

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