Alzheimer's Disease (AD) presently afflicts more than million individuals in the U.S., and this number will increase as the population ages. Published and unpublished preliminary studies have shown that amyloid beta peptides (Abeta) directly activate the complement system in vitro leading to the formation of covalent complexes of Abeta with C3 activation products and to generation of the pro-inflammatory C5a and C5b- complement activation products. These in vitro findings provide potential inflammation based mechanisms to account for the presence of complement components in neuritic plaques (NP) in the AD brain together with damaged neurons and increased numbers of activated glial cells and neuronal damage. In the proposed studies, we will utilize a recently developed murine transgenic (tg) model of AD to evaluate complement and pro-inflammatory cytokine-mediated inflammatory processes in the pathogenesis and progression of AD. These studies are encompassed in the following three specific aims: 1. Molecular and functional analysis of the role of the complement system in the development of AD in AD tg mice. Abeta deposition, complement protein deposition, C5b-9 generation, NP formation with astrocyte and microglia activation and influx, and neuronal damage in the brain will be tracked as a function of time in AD tg mice, and in AD tg mice crossed with C5 deficient, and C3, CR1/CR2 and C5a receptor knockout novel functions of C5 in neuronal homeostasis will also be sought. 2. Molecular and functional analysis of the role of pro-inflammatory cytokines in the development of AD in AD tg mice. The same parameters will be tracked in AD tg mice, and in AD tg mice crossed with pro- inflammatory cytokine (IL-1, IL-6, TNF-alpha) knockout mice as a function of time. 3. Evaluation of the effects of persistent neuronal expression of a neurotropic viral gene product (LCMV NP) or an aberrant host protein (PrP/SC) on the development of AD in AD tg mice. The kinetics of AD development in AD tg mice crossed with NSE-LCMV NP and AD tg mice crossed with NSE-hamster PrP mice inoculated with hamster scrapie will be assessed in collaboration with M. Oldstone. These studies will definitively show whether complement and pro- inflammatory cytokines play major roles in the pathogenesis and progression of AD. A demonstration of critical roles for complement and cytokines in AD will offer numerous potential targets for the development of therapeutic agents to prevent or treat AD.
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