Study on cholesterol-dependent regulatory mechanisms of amyloid precursor protein processing in lipid microdomains

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Lipid rafts are membrane microdomains in which cholesterol is one of the major components. In vitro and in vivo studies have shown that intracellular cholesterol levels have a great impact on the processing of amyloid precursor protein (APP) to amyloid-β peptide (Aβ), the major constituent of senile plaques. Since APP and amyloidogenic APP-cleaving enzymes (β- and γ-secretases) have all been found in lipid rafts, the microdomain will be a critical site for cholesterol-dependent regulation of Aβ production.We hypothesize that partitioning of APP into the lipid rafts is controlled by interaction between APP and a raft protein(s) and that it regulates access to amyloidogenic secretases. To search for candidate proteins in rafts, we isolated lipid rafts from mouse brains or primary cultured cortical neurons and then performed immuno-isolation of APP-containing rafts. Characterization of protein components of the immuno-isolated rafts indicated functional specialization of APP-containing rafts for intracellular vesicular transport in neurons. Several proteins rich in the trans-Golgi network/endosomes are found in APP-containing rafts as well as in γ-secretase-containing ones, suggesting lipid rafts in such organelles may be involved in cholesterol-dependent regulation of Aβ production.Further analyses of immuno-isolated rafts and their protein components will provide new insights into raft-related regulatory mechanisms of APP processing in neurons.