Overexpression of calsenilin enhances γ-secretase activity

Presenilin/γ-secretase is a membrane-associated protease that cleaves within the transmembrane region of the amyloid precursor protein (APP) to generate amyloid-β peptide (Aβ) whose deposition in the brain is a characteristic of Alzheimer's disease (AD). Calsenilin, a calcium binding protein that has been shown to interact with the C-termini of both presenilin 1 (PS1) and presenilin 2 (PS2), appears to play a role in transcriptional regulation and apoptosis and to bind to A-type voltage-gated potassium channels. Here, we report that overexpression of calsenilin enhanced γ-secretase activity in cells. The effect of calsenilin on the γ-cleavage of substrates was blocked by the selective γ-secretase inhibitor L-685,458. We also employed a cellular γ-cleavage GFP-reporter assay to demonstrate the effect of calsenilin on γ-secretase activity. To establish a direct role for calsenilin in regulating γ-secretase activity, we incubated purified calsenilin with isolated membrane fractions and found increased Aβ production in a cell free system. These data suggest that calsenilin may be one of the regulatory factors for γ-secretase.