APP-BP1 inhibits Aβ42 levels by interacting with Presenilin-1

Background: The beta-amyloid precursor protein (APP) is sequentially cleaved by the beta- and then gamma-secretase to generate the amyloid beta-peptides A beta 40 and A beta 42. Increased A beta 42/A beta 40 ratios trigger amyloid plaque formations in Alzheimer's disease (AD). APP binds to APP-BP1, but the biological consequence is not well understood. Results: We report that when the endogenous APP-BP1 was suppressed by small interfering RNAs (siRNAs), cell-associated A beta 42 was dramatically increased in APP(695) expressing primary neurons. The accumulation of A beta 42 was accompanied by significant increases in APP and APP-CTF in APP-BP1 siRNA expressing neurons. In contrast, APP-BP1 overexpression in primary neurons significantly decreased the levels of A beta and endogenous APP but not APLPs. We also investigated the potential mechanism of APP-BP1-mediated APP processing. APP-BP1 co-precipitated with Presenilin-1 (PS1) in native rat brain extracts, co-migrated with the gamma-secretase components in brain membrane extracts in glycerol gradient centrifugation, and colocalized in primary neurons. Further, the endogenous PS1-CTF was significantly downregulated by APP-BP1 expression. Conclusion: Our data suggest that APP-BP1 may inhibit A beta 42 production by interacting with PS1 under physiological conditions.