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.
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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.
| Type: | Article |
|---|---|
| Title: | Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a Drosophila model of Alzheimer's disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.RA118.003319 |
| Publisher version: | https://doi.org/10.1074/jbc.RA118.003319 |
| Language: | English |
| Additional information: | This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions. |
| 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 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10073714 |
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