The common pathologic processes manifest as Alzheimer's disease (AD) likely impact on very basic aspects of cell biology. In the investigation of glial and neuronal interactions, cell culture approaches offer a degree (and rate) of manipulation unavailable in other models. Therefore, we propose to test in tissue culture various aspects of the cytokine cycle theoretically operative in AD. Primary microglial cultures, neuronal cultures, and relevant cell lines will be utilized to assay the effects of S100beta and Abeta on parameters deemed crucial by the other projects to the initiation of progression of AD and related conditions. The essential hypothesis driving this project is that products of betaAPP (including Abeta) stimulate glial responses exacerbated by the glial cytokines S100beta and IL-1 that result in excitotoxicity. Furthermore, we see the rapid screening opportunities available in cell culture as an indispensable tool for testing anti-inflammatory agents against an effect of Abeta that may create dire complications for immunization therapies for AD. Therefore, this project will focus on the following specific aims: (1) Characterize the molecular mechanisms through which S100beta control s the betaAPP gene promoter, (2) determine the potential contribution of excitotoxi8c amino acids to microglial toxicity, (3) determine the effectiveness of anti-inflammatory cytokines and drugs against Abeta induction of a key cytokine, and (4) determine the biological effects of polymorphisms in the IL-1 gene. Accomplishment of these goals will be of direct benefit to the identification of basic elements of AD pathogenesis and potential sites for therapeutic intervention.
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