A-BETA INFUSION INDUCED DEPOSITION, INFLAMMATION AND NEUROTOXICITY

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Strong genetic evidence links familial Alzheimer Disease (FAD) mutations to increased amyloid beta protein (Abeta) production. A major remaining problem for the amyloid cascade hypothesis is that when the FAD genes which increase Abeta production are put in APP transgenic mouse model for AD pathogenesis, they show extensive amyloid plaques, but lack quantifiable neuron loss, making their use in studying neuroprotective strategies problematic. One might hypothesize that over- expression of APP required to induce amyloid deposits, results in over- expression of neuroprotective APP domains as well as poorly understood intrinsic neuroprotective mechanisms (Bcl-2, antioxidant defenses, Abeta degradation systems etc) or that beta-amyloid is not very toxic in mice. Rodent infusion models allow separation of APP versus Abeta effects and facilitate investigation of co-factors that modulate deposition and co- factors. In this proposal we investigate a lipoprotein-mediated method of chronic delivery of Abeta to the brain parenchyma in rats that results in widespread diffuse deposits as well as neurotoxicity and quantifiable reactive gliosis. We will use this Abeta infusion model to: (1) To characterize and compare the effects of intraventricular co- infusion of Abeta and ApoE isoform enriched HDL derived from E3/3 AND E4/4 donors (Genetics Core) or known glia-derived, CNS apolipoprotein carriers (Apo E isoforms) on Abeta deposition, neurotoxicity and microglial activation. (2) To determine whether neuron damage in rat brains from Aim 1 and in AD brain (Pathology Core) will correlate better with microglial activation, soluble Abeta levels or insoluble Abeta levels. (3) To investigate whether inhibition of fibril formation or regression of diffuse plaques can decrease or increase Abeta-induced neurotoxicity and gliosis in vivo. (4) To test the role of complement activation in Abet infusion-induced neurotoxicity and deposition using rats treated with complement inhibitors or C3 knockout mice. (5) We will determine the relative effects of brain permeable phenolic anti-oxidants and steroidal anti-inflammatory agents on Abeta-induced microglial activation, gliosis, neurotoxicity and Abeta deposition, comparing the efficacy of these drugs to the complement inhibitors used in aim 4.