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

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Cholesterol-dependent cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1) in lipid rafts is thought to be a critical regulatory event in generating amyloid-beta peptide, which plays a key role in the pathogenesis of Alzheimer's disease. To investigate the underlying molecular mechanisms of this process in neurons, we analyzed immunoisolated, APP-containing, detergent-resistant membranes from mouse and rat brains. APP was incorporated into cholesterol-dependent lipid-protein complexes linked through a network of protein interactions, which largely excluded BACE1. In copatching experiments, APP was preferentially associated with microdomains marked by GPI-anchored prion protein and not BACE 1-containing microdomains. Protein interactions were necessary for association with the prion-containing microdomains and mediated inhibitory effects on APP-BACE1 interaction and beta-cleavage. Thus we propose a novel regulatory mechanism of APP processing through differential association with distinct microdomains controlled by protein interactions.