BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2.
Alzheimer disease (AD) is characterized by senile plaques, which are mainly composed of beta amyloid (Abeta) peptides. Abeta is cleaved off from amyloid precursor protein (APP) with consecutive proteolytic processing: beta-secretase, followed by gamma-secretase. Here, we show that BRI3, a member of the BRI gene family that includes the familial British and Danish dementia gene BRI2, interacts with APP and serves as an endogenous negative regulator of Abeta production. BRI3 colocalizes with APP along neuritis in differentiated N2a cells; endogenous BRI3-APP complexes are readily detectable in mouse brain extract; reducing endogenous BRI3 levels by RNA interference results in increased Abeta secretion. BRI3 resembles BRI2, because BRI3 overexpression reduces both alpha- and beta-APP cleavage. We propose that BRI3 inhibits the various processing of APP by blocking the access of alpha- and beta-secretases to APP. However, unlike BRI2, the binding of BRI3 to the beta-secretase cleaved APP C-terminal fragment is negligible and BRI3 does not cause the massive accumulation of this APP fragment, suggesting that, unlike BRI2, BRI3 is a poor gamma-cleavage inhibitor. Competitive inhibition of APP processing by BRI3 may provide a new approach to AD therapy and prevention.
Matsuda
Shuji
S
Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York 1046, USA.
Matsuda
Yukiko
Y
D'Adamio
Luciano
L
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000235:genetics / Q000517:prevention & control; D000682:Amyloid / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D018388:Codon, Terminator; D017931:DNA Primers; D003704:Dementia / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014162:Transfection
C084104:APLP2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; C499959:BRI3 protein, human; D018388:Codon, Terminator; D017931:DNA Primers; C120083:ITM2B protein, human; C492300:Itm2b protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins