BACE2, a b-secretase homolog, cleaves at the b site and within the amyloid-b region of the amyloid-b precursor protein

Production of amyloid-b protein (Ab) is initiated by a b-secretase that cleaves the Ab precursor protein (APP) at the N terminus of Ab (the b site). A recently identified aspartyl protease, BACE, cleaves the b site and at residue 11 within the Ab region of APP. Here we show that BACE2, a BACE homolog, cleaves at the b site and more efficiently at a different site within Ab. The Flemish missense mutation of APP, implicated in a form of familial Alzheimer’s disease, is adjacent to this latter site and markedly increases Ab production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative b-site mutations, and alteration of a common active site Arg inhibits b-site cleavage but not cleavage within Ab by both enzymes. These data suggest that BACE2 contributes to Ab production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous.