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

Production of amyloid-beta protein (A beta) is initiated by a beta-secretas e that cleaves the A beta precursor protein (APP) at the N terminus of A be ta (the beta site). A recently identified aspartyl protease, BACE, cleaves the beta site and at residue 11 within the A beta region of APP. Here we sh ow that BACE2, a BACE homolog, cleaves at the beta site and more efficientl y at a different site within AP. The Flemish missense mutation of APP, impl icated in a form of familial Alzheimer's disease, is adjacent to this latte r site and markedly increases A beta production by BACE2 but not by BACE. B ACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within A beta by both enzymes. These data suggest that BACE2 contr ibutes to A beta production in individuals bearing the Flemish mutation, an d that selective inhibition of these highly similar proteases may be feasib le and therapeutically advantageous.