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

Edgar, James R; Willén, Katarina LU ; Gouras, Gunnar K and Futter, Clare E (2015) In Journal of Cell Science 128(14). p.2520-2528
Abstract
Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) 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 endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited... (More)
Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) 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 endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes and lead 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Cell Science
volume
128
issue
14
pages
2520 - 2528
publisher
The Company of Biologists Ltd
external identifiers
  • pmid:26002056
  • wos:000359771300012
  • scopus:84937942782
ISSN
0021-9533
DOI
10.1242/jcs.170233
language
English
LU publication?
yes
id
75d78260-dc1e-43e5-a7d0-6bedaceab02b (old id 5442572)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26002056?dopt=Abstract
date added to LUP
2015-06-05 11:53:39
date last changed
2017-11-12 03:12:58
@article{75d78260-dc1e-43e5-a7d0-6bedaceab02b,
  abstract     = {Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) 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 endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes and lead 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.},
  author       = {Edgar, James R and Willén, Katarina and Gouras, Gunnar K and Futter, Clare E},
  issn         = {0021-9533},
  language     = {eng},
  number       = {14},
  pages        = {2520--2528},
  publisher    = {The Company of Biologists Ltd},
  series       = {Journal of Cell Science},
  title        = {ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular beta amyloid accumulation.},
  url          = {http://dx.doi.org/10.1242/jcs.170233},
  volume       = {128},
  year         = {2015},
}