The proposed studies will continue investigations into the nature of the selection process that leads to degenerative changes in the brains of humans with Alzheimer's Disease (AD). AD is recognized is one of the major public health and quality-of-life problems facing the world community. AD is characterized by a distinct set of neuropathological lesions, e.g. senile plaques,a nd the death of selected neural systems. Inflammatory processes play an as yet undefined role in the pathogenesis of AD. The studies will investigate the biochemical, histopathological and behavioral consequence of chronic exposure to inflammatory agents within the brain of normal rats and rats that over-express human beta-amyloid. The project will test the hypothesis that inflammatory processes are involved in the initial stages of cellular dysfunction that may alter cellular vulnerability to endogenous toxins; these changes may in turn lead to cell death. In addition, the Pi will investigate whether there is an age-associated increase in the vulnerability to these processes. Finally, because the cascade of biochemical processes that leads to neuronal degeneration may involve the activation of NMDA receptors, the production of nitric oxide or prostaglandins, or the activation of interleukin-1 receptors, the studies will also investigate whether it is possible to antagonize these processes and provide neuroprotection.
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