APP-BPI inhibits Aβ42 levels by interacting with presenilin-I

Abstract

Background: The β-amyloid precursor protein (APP) is sequentially cleaved by the β- and then y-secretase to generate the amyloid β-peptides Aβ40 and Aβ42. Increased Aβ42/Aβ40 ratios trigger amyloid plaque formations in Alzheimer's disease (AD). APP binds to APP-BPI, but the biological consequence is not well understood. Results: We report that when the endogenous APP-BPI was suppressed by small interfering RNAs (siRNAs), cell-associated Aβ42 was dramatically increased in APP 695 expressing primary neurons. The accumulation of Aβ42 was accompanied by significant increases in APP and APP-CTF in APP-BPI siRNA expressing neurons. In contrast, APP-BPI overexpression in primary neurons significantly decreased the levels of Aβ and endogenous APP but not APLPs. We also investigated the potential mechanism of APP-BPI-mediated APP processing. APP-BPI co-precipitated with Presenilin-l (PSI) in native rat brain extracts, co-migrated with the γ-secretase components in brain membrane extracts in glycerol gradient centrifugation, and colocalized in primary neurons. Further, the endogenous PSI-CTF was significantly downregulated by APP-BPI expression. Conclusion: Our data suggest that APP-BPI may inhibit Aβ42 production by interacting with PSI under physiological conditions.