The objective of this Program Project is to critically evaluate a hypothesized cytokine cycle of molecular and cellular events that we propose is important in the pathogenesis of Alzheimer disease. Effector- stimulated microglial activation with synthesis and release of the glial inflammatory cytokine interleukin-1 (IL-1) is seminar in this cycle. IL- 1-based actions include (i) induction of over-expression and processing of beta-amyloid precursor protein (betaAPP) in neurons (leading to beta- amyloid deposition, cell death and release of secreted APP, stimulating further expression of IL-1); and (ii) activation of astrocytes and release of S100beta (increasing the potential for cell death by promoting increases in intraneuronal calcium, by promoting synthesis of beta-APP, and by inducing overgrowth of dystrophic neurites) and with synthesis and release of ApoE (which may bind to beta-amyloid and stabilize it). Alzheimer's disease is inherently progressive, and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must explain this progression., and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must explain this progression. We postulate, in view of IL-1 based actions, and the potential of chronic IL-1 over-expression to promote neuronal injury and death, that the progression of Alzheimer's disease may be driven by this potentially self propagating, self sustaining sequence events. We will determine the role of glial inflammatory processes in neuronal cell injury and death in Alzheimer's disease and in epilepsy, which predisposes to early Alzheimer-type changes. We will also determine temporal and spatial relationships between glial inflammatory processes and neuronal cell injury and death in Down's syndrome and following head injury, and the modulating effects of genotype on these processes. We will also use transgenic animals over-expressing S100beta or betaAPP to define mechanisms responsible for these relationships. Cell culture models will be used to define mechanisms by which glial inflammatory proteins modulate neuronal cell injury and death. Accomplishment of the goals of this Program will yield results of direct benefit to the identification of basic elements in Alzheimer pathogenesis and provide targets for development of therapeutic strategies.
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