title: APP-BP1 inhibits Abeta42 levels by interacting with Presenilin-1.
abstract: BACKGROUND
  The beta-amyloid precursor protein (APP) is sequentially cleaved by the beta- and then gamma-secretase to generate the amyloid beta-peptides Abeta40 and Abeta42. Increased Abeta42/Abeta40 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 Abeta42 was dramatically increased in APP695 expressing primary neurons. The accumulation of Abeta42 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 Abeta 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.
  
  
  CONCLUSIONS
  Our data suggest that APP-BP1 may inhibit Abeta42 production by interacting with PS1 under physiological conditions.
authors.affiliation: Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. chenyuzhi@uams.edu
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Chen
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bodles
authors.forename: Donna L
authors.initials: DL
authors.lastname: McPhie
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Robert E
authors.initials: RE
authors.lastname: Mrak
authors.forename: W Sue T
authors.initials: WS
authors.lastname: Griffin