Disruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage.

ABSTRACT: Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid β (Aβ) peptide, derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affecting APP accumulation, ubiquitination of cytodomain lysines may represent a key signal controlling APP endosomal sorting. Here, we show that substitution of APP C-terminal lysines with arginine disrupts APP ubiquitination and that an increase in the number of substituted lysines tends to increase APP metabolism. An APP mutant lacking all C-terminal lysines underwent the most pronounced

SUBMITTER: Williamson RL 

PROVIDER: S-EPMC5712626 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature