Apolipoprotein E (apoE), a lipid transport protein, has been implicated in cardiovascular disease and Alzheimer's disease (AD). ApoE, in normal levels, promotes receptor-mediated clearance of lipoprotein remnants from circulation and protects from atherosclerosis. ApoE, synthesized by astrocytes and neurons, interacts with other brain proteins and affects the development of AD. Recent studies have shown that cholesterol is a risk factor for AD. ApoE interacts with the ABCA1 lipid transporter promoting cholesterol efflux and with the SR-BI HDL receptor promoting both cholesterol efflux and cholesteryl ester uptake, thus affecting cholesterol homeostasis in cells and tissues. Both ABCA1 and SR-BI are expressed in macrophages, liver and brain.
It is possible that disturbances in lipid homeostasis may contribute to the neurodegeneration observed in AD. The objective of this proposal is to systematically study the functional interactions of apoE with ABCA1 and SR-BI. These interactions lead to the formation or remodelling of apoE-containing HDL-like lipoproteins and affect cholesterol homeostasis in circulation and brain. I propose to produce wild type and mutant apoE forms, containing targeted point mutations and deletions, using an adenovirus expression system and use them to investigate how structural alterations in apoE affect its functional interactions (binding, cholesterol efflux, cholesteryl ester uptake) with ABCA1 and SR-BI. I also propose to map the domains or residues of apoE involved in the formation and remodelling of apoE-containing HDL-like lipoproteins in brain, by using adenovirus-mediated gene transfer of apoE variants in brain slice cultures.
The proposed studies are expected to enhance our understanding of the mechanisms of apoE mediated cholesterol transport in circulation and particularly in the brain. This information may lead to new therapeutic insights for the prevention or treatment of cardiovascular disease and AD.
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