BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis

Mutations in amyloid beta precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, beta-siteAPPcleaving enzyme 1 (BACE1) cleavesAPPat minor Asp1 site to generate C99 for amyloid beta protein (A beta) production, and predominantly at major Glu(11) site to generate C89, resulting in truncated A beta production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential beta-cleavage site of BACE1 in APP from the Glu(11) site to the Asp(1) site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate A beta, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis inADpathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.