A novel microdomain-dependent regulatory mechanism of amyloid precursor protein processing

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Beta-cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) in a membrane microdomain is thought to be a critical regulatory event in generating β-amyloid which is central to the pathogenesis of Alzheimer's disease. To investigate the underlying molecular mechanisms of this process, we analyzed immunoisolated, APP-containing, detergent-resistant membranes from mouse brains. APP was associated with cholesterol-dependent microdomains through a network of protein interactions involving X11, Munc18 and syntaxin 1, which largely excluded BACE1. APP-X11-Munc18 interaction mediated inhibitory effects on APP-BACE1 interaction and β-cleavage. We propose a novel regulatory mechanism of APP processing involving microdomain segregation that depends on protein-protein interactions and is controlled by cdk5 phosphorylation.