S286 S~mposiun: The Role qf It$‘ammation in Alzheimer’s Disease

113041 SUPPRESSION OF MICROGLIAL INJURY TO NEURONS IN ALZHEIMER’S DISEASE

Reactive microgliosis is thought to contribute to the neuronal pathology of AD by the release of neurotoxic agents. The inhibition of neurotoxic microglia, activated by contact with plaques, may reduce immune-mediated brain injury, and, in turn, slow disease progression. Despite enthusiasm for immune suppression as a treatment for AD, many unanswered questionr must be addressed before a focused clinical trial can be designed. Here, the use of in vitro and in viva preclinical models are described for screening of microglial suppressants.

CYTOKINES AND ALZHEIMER’S DISEASE

SW T. Grr$j?n. M&I&m VA Medicrrl Center, Little Rock. AR. AR

Our early idea that specific glia-derived cytokines are overexpressed in response to neuropathological changea in Alzheimer brain, and that this overexpresaion contrib- ute$ to further changes and further cytokine overexpression, was a departure from more conventional ideas regarding Alzheimer pathogen&s. Our demonstration of mterleukin-I (IL- I) overexpression in Alzheimer brain was the first evidence wpporting this controversial new idea. This overexpression ia principally derived from activated microglia, and is directly related to the progression of amyloid deposits into diagnortic neuritic P-amyloid plaques and with the spread of pathology across brain regions. The central and important role of IL-l in Alzheimer pathogen&s has been supported by our recent studies showing that specific polymorphisms in IL-1 genes increase risk for Alrheimer’a diaeax. In addition, support i? afforded by other observations showmg that IL-I overexpwaion: i) induces excessive synthesis and processing of the P-amyloid precursor protein (PAPP) in neurons: ii) increases activity and expression of neuronal acetylcholineateraae in vitro and in viva; iii) is associated with neuronal tangle formatlo”, mcreased expression of phosphorylated neurofilament and tau proteins; iv) with neuronal DNA damage and caspase-l expression; v) regulates the synthesis of a number of plaque-associated proteins; and vi) activates aatrocytes with the important consequence of astrocytic overexpression of the neuritogenic cytokine SIOOP. IL-l-induced synthesis of SlOOp provides a link whereby IL-1 contributes to the proliferation of dystrophic neurites and thus to the conversion of P-amyloid deposits into the diagnostic neuritic P-amyloid plaques m Alzheimer’\ disease. Thi\ latter ia supported by our findings that overexpression of biologically active SItlO!. in Alzheimer brain is related to the density of neuritic plaques in and across brain regions, and with the proliferation of dystrophic neurite? m individual plaques. Taken together or separately, these findings we consistent with our hypotheaih that IL-I overexpreaaion in Allheimer’s dibeabe I\ critical in driving progressive lo\\ of neurons as well as progre\\ive accumulation of neuritic P-amyloid plaquch. Support. AGI2JI I.

pikg THE ROLE OF INFLAMMATION IN THE CLINICAL PROGRES- SION OF ALZHEIMER’S DISEASE DEMENTIA

Giulio Maria Pasinetti. Mount Sinai School of Medicine, New York, NY

Little is known about the molecular mechanisms involved in the clinical progression of Alzheimer’s disease (AD). Prior studies have shown that cyclooxygenase-2 (COX-2). an enzyme involved in inflammatory mechanisms as well as neuronal processes, is upregulated in AD brain and may represent a therapeutic target. In this study, we found that the intensity of COX-2 expression in the CA3 and CA2 but not CAI subdivisions of the pyramldal layers of the hippocampal formation of AD brain increases as the disease progressed from questionable to mild clinical dementia as assessed by clinical dementia rating (CDR). COX-2 signal was increased in all the three regions examined among cases characterized by severe dementia. This change in neuronal COX-2 protein content preceded the elevation of cytokine expression (cortical IL-6 and TGF-PI signal) at later CDR stages. This suggests that COX-2 expression is upregulated early in the clinical progression of the disease before there might be significant intlammatton in the brain. Therefore, our studies support the theory that non-steroidal anti-inflammatory drug (NSAIDs) wed in the prevention of early treatment of AD may affect neuronal COX-2, and may not be exerting a classical anti-intlammatory effect on later cytokine mediated inflammatory condi- tions. On the other hand, drugs (e.g. hydroxychloroquine and colchicine) aimed at suppressing cytokine mediated activities, such as glial reactivities may be more appropriate at later stages during the course of the disease. In conclusion, these studies substantiate the theory that understanding specific inflammatory processes that have distinct relationships with clinical disease progression is essential to the design of preventive treatment strategies.

pifiq EPIDEMIOLOGIC STUDIES OF NONSTEROIDAL ANTI-IN- FLAMMATORY DRUGS AND ALZHEIMER’S DISEASE

Cluudiu Kuwuv, Johns Hopkins Universin School of Medicine. Baltinrorr, MD

Epidemiologic studies and short-term clinical trials, particularly of nonsteroidal anti-inflammatory drugs (NSAIDS), have added support to the hypothesis that pharmacological suppression of inflammation may slow the rate of Alzheimer pathology. Epidemiologic observations have included twin and sibling atudiea (Breitner et al. 1994, 1995). population based studies (Anderson et al. 1995). and longitudinal studies of patients with AD (Rich et al. 1995). In the Baltimore Longitudinal Study of Aging (Stewart et al. 1997). prospective data suggested that use of NSAIDs for more than two years may reduce the risk of AD by approximately one half. These wdies, as well as others identified by McGeer et al. 1996, will be reviewed. Together, they suggest a protective effect of anti-inflammatory agents, but there have also been numerous studies that do not confirm these effects. Some investigations have even suggested an inverse relationship between the use of NSAlDs and the maintenance of cognitive abilities (Founier et al. 1996; Saag et al. 1995). Further understanding of these finding? requires randomized clinical tnals, \ome of which are currently underway