Inheritance of the E4 allele of apolipoprotein E (apoE) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is associated with increased deposition of amyloid B protein (AB). The goal of this proposal is to elucidate the role of apoE in the metabolism of AB and amyloid precursor protein (APP) and its control by dietary cholesterol. The studies in this proposal are based on the working hypothesis that the absolute level of apoE is a major determinant of AB levels in the brain and can be regulated by dietary cholesterol. Our preliminary studies show that physiological concentrations of apoE significantly elevate the levels of the 40 and 42 amino acid forms of AB in human cortical cultures due to inhibition of AB degradation. Moreover, rats fed a high cholesterol diet show significantly elevated apoE levels in the cerebral cortex and altered processing of APP. These findings suggest that increased cortical apoE, which can be induced by a high cholesterol diet, may predispose to AB deposition and the onset of AD. The effect of apoE on the cortical metabolism of AB and APP will be investigated in apoE-knockout and apoE3 and apoE4-transgenic mice. We will determine whether apoE has the greatest effect on AB metabolism in the aging brain, and whether this effect can be modulated by dietary cholesterol. These studies will be complemented by an investigation of the effects of apoE and dietary cholesterol on plaque formation in APP-transgenic mice, and the examination of potential therapeutic approaches utilizing cholesterol-lowering drugs and neural stem cells that can scavenge apoE. The effect of a high cholesterol diet on AB production in transgenic mice that express disease-causing presenilin-1 mutations will also be examined. To elucidate the mechanism by which apoE inhibits AB degradation; the receptors and soluble factors that mediate AB clearance will be identified in primary human cortical cultures. Known candidate receptors that could mediate AB uptake, including the LDL receptor-related protein, the microglial scavenger receptor and the serpin-enzyme complex receptor, will be examined, as well as novel AB uptake receptors. These studies may help to elucidate the roles of apoE and dietary cholesterol in the pathogenesis of AD, with potentially important implications for early genotyping and therapeutic intervention.
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