ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-? accumulation.

ABSTRACT: Intracellular amyloid-? (A?) accumulation is a key feature of early Alzheimer's disease and precedes the appearance of A? in extracellular plaques. A? is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of A? production is unclear. APP has been localized to multivesicular bodies (MVBs) where sorting of APP onto intraluminal vesicles (ILVs) could promote amyloidogenic processing, or reduce A? production or accumulation by sorting APP and processing products to lysosomes for degradation. Here, we show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and that it is delivered to lysosomes for degradation. Depletion of the endosomal sorting complexes required for transport (ESCRT) components, Hrs (also known as Hgs) or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes, and led to increased intracellular A? accumulation. This was accompanied by dramatically decreased A? secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular A? accumulation through targeting of APP and processing products to the lysosome for degradation, and promoting A? secretion.

SUBMITTER: Edgar JR 

PROVIDER: S-EPMC4510853 | biostudies-other | 2015 Jul

REPOSITORIES: biostudies-other