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J Cell Sci. 2015 Jul 15;128(14):2520-8. doi: 10.1242/jcs.170233. Epub 2015 May 22.

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

Author information

1
Department of Cell Biology, UCL Institute of Ophthalmology, London EC1 V9EL, UK Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
2
Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
3
Department of Cell Biology, UCL Institute of Ophthalmology, London EC1 V9EL, UK c.futter@ucl.ac.uk.

Abstract

Intracellular amyloid-β (Aβ) accumulation is a key feature of early Alzheimer's disease and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ 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 Aβ 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 Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation, and promoting Aβ secretion.

KEYWORDS:

Alzheimer's disease; Amyloid precursor protein; ESCRT; Multivesicular body

PMID:
26002056
PMCID:
PMC4510853
DOI:
10.1242/jcs.170233
[Indexed for MEDLINE]
Free PMC Article

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