Although genetic mutations increasing beta-amyloid peptide 1-42 (Abeta42) production are linked to Alzheimer's disease (AD), most AD cases do not appear linked to genetic factors increasing Abeta production, but rather to ApoE4 and unidentified genetic and environmental factors which result in more Abeta deposition. Since ApoE4 containing lipoproteins can carry Abeta, ApoE4 may lead to more Abeta deposition by a failure to degrade or clear Abeta. Reduced clearance result from increased aggregation and fibril formation or reduced delivery of Abeta to lysosomes. Abeta deposits per se, such as diffuse Abeta deposits are not closely linked to neurodegeneration or clinical deficits, arguing that some additional factor may be rate limiting in Alzheimer's disease pathogenesis. Mounting evidence from many sources suggests that response to injury and microglial activation may be limiting factors and appropriate therapeutic targets. we propose to use 1) pharmacological and 2) genetic tools to explore the role of microglia in plaque pathogenesis, using a transgenic mouse model in which we show microglial activation linked to Abeta plaque formation. we will 3) study the role of ApoE isoforms in microglia/ Abeta interactions in vitro; 4) examine the effects of apoE isoforms on Abeta clearance and deposition in brains of transgenic mice, and 5) test the effects of ApoE isoforms on plaque formation in vivo and on clearance (degradation and removal) and deposition in organotypic cultures. These experiments will provide new information on the role of microglia and ApoE4 in plaque pathogenesis and CNS Abeta metabolism.
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