Beta-secretase/BACE1 promotes APP endocytosis and processing in the endosomes and on cell membrane.

Amyloid-β proteins deposition and aggregation occur in extracellular space and form neuritic plaques in Alzheimer's disease (AD) brain. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)/ β-secretase and γ-secretase Presenilin 1 (PSEN1) conduct sequential cleavage of amyloid- β precursor protein (APP) and yield amyloid- β proteins. However the details of the interactions of APP with the enzymes and transportation of catalytic products are unclear. Here we reveal distinctive targeting patterns of the proteins in subcellular organelles in N2A cells. We find all three proteins co-localize in endosomes with APP and PSEN1 co-localize and associate on cell membrane and nucleus. By selectively knocking down BACE1 or PSEN 1 with siRNA, we discover that BACE1 functions as the enzyme initiating the first cleavage step and serves a scaffold for APP and PSEN1 endocytosis. PSEN1 knocking-down only leads to the reduction of BACE1 in cell membrane and nucleus. We conclude that BACE1 facilitates the transportation of APP and formation of the complex with γ-secretase, resulting in the stepwise cleavages of APP. After BACE1 cleavage APP binds to PSEN1 and transfers to cell membrane or nucleus for final processing and amyloid genesis.