eprintid: 10073714
rev_number: 23
eprint_status: archive
userid: 608
dir: disk0/10/07/37/14
datestamp: 2019-05-15 13:48:38
lastmod: 2021-12-05 00:39:10
status_changed: 2019-05-15 13:48:38
type: article
metadata_visibility: show
creators_name: Younan, ND
creators_name: Chen, K-F
creators_name: Rose, R-S
creators_name: Crowther, DC
creators_name: Viles, JH
title: Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a Drosophila model of Alzheimer's disease
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F81
keywords: Alzheimer's disease, Drosophila, amyloid-beta (AB), animal model, circadian rhythm, fibril, neurodegenerative disease, oligomer, prion, protein misfolding, Alzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Circadian Rhythm, Disease Models, Animal, Drosophila melanogaster, Longevity, Mesocricetus, Neurotoxicity Syndromes, Prion Proteins, Protein Binding, Protein Multimerization
note: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: The cellular prion protein (PrPC) can act as a cell-surface receptor for β-amyloid (Aβ) peptide; however, a role for PrPC in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of Aβ isoforms and PrPC in the Drosophila brain. We found that co-expression of Aβ and PrPC significantly reduces the lifespan, disrupts circadian rhythms, and increases Aβ deposition in the fly brain. In contrast, under the same conditions, expression of Aβ or PrPC individually did not lead to these phenotypic changes. In vitro studies revealed that substoichiometric amounts of PrPC trap Aβ as oligomeric assemblies and fragment-preformed Aβ fibers. The ability of membrane-anchored PrPC to trap Aβ as cytotoxic oligomers at the membrane surface and fragment inert Aβ fibers suggests a mechanism by which PrPC exacerbates Aβ deposition and pathogenic phenotypes in the fly, supporting a role for PrPC in AD. This study provides a second animal model linking PrPC expression with Aβ toxicity and supports a role for PrPC in AD pathogenesis. Blocking the interaction of Aβ and PrPC represents a potential therapeutic strategy.
date: 2018-08-24
date_type: published
official_url: https://doi.org/10.1074/jbc.RA118.003319
oa_status: green
full_text_type: pub
pmcid: PMC6109938
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1584272
doi: 10.1074/jbc.RA118.003319
pii: RA118.003319
lyricists_name: Chen, Ko-Fan
lyricists_id: KCHEA78
actors_name: Allington-Smith, Dominic
actors_id: DAALL44
actors_role: owner
full_text_status: public
publication: Journal of Biological Chemistry
volume: 293
number: 34
pagerange: 13090-13099
event_location: United States
issn: 1083-351X
citation:        Younan, ND;    Chen, K-F;    Rose, R-S;    Crowther, DC;    Viles, JH;      (2018)    Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a Drosophila model of Alzheimer's disease.                   Journal of Biological Chemistry , 293  (34)   pp. 13090-13099.    10.1074/jbc.RA118.003319 <https://doi.org/10.1074/jbc.RA118.003319>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10073714/1/Chen_J.%20Biol.%20Chem.-2018-Younan-13090-9.pdf