Amyloid- protein (A) Glu11 is the major -secretase site of -site amyloid- precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to A Asp1 contributes to Alzheimer pathogenesis

Cleavage of amyloid- precursor protein (APP) at the Asp1 -secretase site of the amyloid- protein (A) domain by -site A precursor protein-cleaving enzyme 1 (BACE1) is required for the generation of A, a central component of neuritic plaques in the Alzheimer's disease (AD) brain. In this study, we found that A Glu11 is the major -secretase site for cleavage of APP by BACE1 to generate soluble secreted APP (sAPP)606 and the C-terminal membrane-bound fragment (CTF) product C89. Cleavage of C89 by -secretase resulted in truncated A generation in a non-amyloidogenic pathway. A familial AD-associated Swedish APP mutation adjacent to A Asp1 shifted the major APP -secretase cleavage site from A Glu11 to Asp1, resulting in significant increases in sAPP596 and CTF C99 generation and the C99/89 ratio, in turn leading to increased A production in cultured cells in vitro and transgenic AD model mouse brains in vivo. Furthermore, increased BACE1 expression facilitated APP being processed by the -secretase processing pathway rather than the -secretase pathway, leading to more A production. Our results suggest that potentiating BACE1 cleavage of APP at both the Asp1 and Glu11 sites, or shifting the cleavage from the Glu11 site to the Asp1 site, could result in increased A production and facilitate neuritic plaque formation. Our study provides new insights into how alteration of BACE1 expression and -secretase cleavage site selection could contribute to Alzheimer pathogenesis and the pharmaceutical potential of modulating BACE1 expression and its cleavage site selection.