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

ABSTRACT: Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, β-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp¹ site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu¹¹ site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu¹¹ site to the Asp¹ 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 l

SUBMITTER: Zhang S 

PROVIDER: S-EPMC6705717 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature