Control of amyloid-beta-peptide generation by subcellular trafficking of the beta-amyloid precursor protein and beta-secretase.

Amyloid-beta (Abeta) peptides are major components of Alzheimer's disease (AD)-associated senile plaques and generated by sequential cleavage of the beta-amyloid precursor protein (betaAPP) by beta-secretase and gamma-secretase. While beta-secretase activity is exerted by the aspartic protease BACE1, gamma-secretase consists of a protein complex of at least four essential proteins with the presenilins as the catalytically active components. The understanding of the subcellular trafficking of betaAPP and proteases involved in its proteolytic processing has increased rapidly in the last years. BetaAPP as well as the secretases are membrane proteins, and recent work demonstrated that alterations in the lipid composition of cellular membranes could affect the proteolytic processing of betaAPP and Abeta generation. We identified glycosphingolipids as membrane components that modulate the subcellular transport of betaAPP and the generation of Abeta. By cell biological and biochemical methods we also characterized the role of BACE1 and its homologue BACE2 in the proteolytic processing of betaAPP. Here, I summarize and discuss these findings in the context of other studies focused on the function of BACE1 and BACE2 and the role of subcellular trafficking in the proteolytic processing of betaAPP. Copyright 2006 S. Karger AG, Basel.