Disruption of amyloid precursor protein ubiquitination selectively increases amyloid beta (A{beta}) 40 levels via presenilin 2-mediated cleavage [Neurobiology]

Amyloid plaques, a neuropathological hallmark 1 of Alzheimer's disease (AD), are largely 2 composed of amyloid beta (Aβ) peptide, derived 3 from cleavage of amyloid precursor protein 4 (APP) by β- and γ-secretases. The endosome is 5 increasingly recognized as an important 6 crossroad for APP and these secretases, with 7 major implications for APP processing and 8 amyloidogenesis. Among various 9 posttranslational modifications affecting APP 10 accumulation, ubiquitination of cytodomain 11 lysines may represent a key signal controlling 12 APP endosomal sorting. Here, we show that 13 substitution of APP C-terminal lysines with 14 arginine disrupts APP ubiquitination and that an 15 increase in the number of substituted lysines 16 tends to increase APP metabolism. An APP 17 mutant lacking all C-terminal lysines underwent 18 the most pronounced increase in processing, 19 leading to accumulation of both secreted and 20 intracellular Aβ40. Artificial APP ubiquitination 21 with rapalog-mediated proximity inducers 22 reduced Aβ40 generation. A lack of APP C- 23 terminal lysines caused APP redistribution from 24 endosomal intraluminal vesicles (ILVs) to the 25 endosomal limiting membrane, with subsequent 26 decrease in APP C-terminal fragment (CTF) 27 content in secreted exosomes, but had minimal 28 effects on APP lysosomal degradation. Both the 29 increases in secreted and intracellular Aβ40 were 30 abolished by depletion of presenilin 2 (PSEN2), 31 recently shown to be enriched on the endosomal 32 limiting membrane compared with PSEN1. Our 33 findings demonstrate that ubiquitin can act as a 34 signal at five cytodomain-located lysines for 35 endosomal sorting of APP. They further suggest 36 that disruption of APP endosomal sorting 37 prevents its sequestration in ILVs and results in 38 PSEN2-mediated processing of a larger pool of 39 APP-CTF on the endosomal membrane.

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