Amyloid-β (Aβ) peptides are major components of Alzheimer’s disease (AD)-associated senile plaques and generated by sequential cleavage of the β-amyloid precursor protein (βAPP) by β-secretase and γ-secretase. While β-secretase activity is exerted by the aspartic protease BACE1, γ-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 βAPP and proteases involved in its proteolytic processing has increased rapidly in the last years. βAPP 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 βAPP and Aβ generation. We identified glycosphingolipids as membrane components that modulate the subcellular transport of βAPP and the generation of Aβ. By cell biological and biochemical methods we also characterized the role of BACE1 and its homologue BACE2 in the proteolytic processing of βAPP. 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 βAPP.

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