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

ABSTRACT: Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid ? (A?) peptide, derived from cleavage of amyloid precursor protein (APP) by ?- and ?-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 increase in processing, leading to accumulation of both secreted and intracellular A?40. Artificial APP ubiquitination with rapalog-mediated proximity inducers reduced A?40 generation. A lack of APP C-terminal lysines caused APP redistribution from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with a subsequent decrease in APP C-terminal fragment (CTF) content in secreted exosomes, but had minimal effects on APP lysosomal degradation. Both the increases in secreted and intracellular A?40 were abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared with PSEN1. Our findings demonstrate that ubiquitin can act as a signal at five cytodomain-located lysines for endosomal sorting of APP. They further suggest that disruption of APP endosomal sorting reduces its sequestration in ILVs and results in PSEN2-mediated processing of a larger pool of APP-CTF on the endosomal membrane.

SUBMITTER: Williamson RL 

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

REPOSITORIES: biostudies-literature