BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis

Deposition of amyloid-beta protein (A beta) to form neuritic plaques is the characteristic neuropathology of Alzheimer's disease (AD). A beta is generated from amyloid precursor protein (APP) by beta- and gamma-secretase cleavages. BACE1 is the beta-secretase and its inhibition induces severe side effects, whereas its homolog BACE2 normally suppresses A beta by cleaving APP/A beta at the theta-site (Phe(20)) within the A beta domain. Here, we report that BACE2 also processes APP at the beta site, and the juxtamembrane helix (JH) of APP inhibits its beta-secretase activity, enabling BACE2 to cleave nascent APP and aggravate AD symptoms. JH-disrupting mutations and clusterin binding to JH triggered BACE2-mediated beta-cleavage. Both BACE2 and clusterin were elevated in aged mouse brains, and enhanced beta-cleavage during aging. Therefore, BACE2 contributes to AD pathogenesis as a conditional beta-secretase and could be a preventive and therapeutic target for AD without the side effects of BACE1 inhibition.