title: ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-β accumulation.
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.
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1 V9EL, UK Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Edgar
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Willén
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
authors.forename: Gunnar K
authors.initials: GK
authors.lastname: Gouras
authors.affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, London EC1 V9EL, UK c.futter@ucl.ac.uk.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D056827:Endosomal Sorting Complexes Required for Transport; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Alzheimer's disease; Amyloid precursor protein; ESCRT; Multivesicular body