TY  - JOUR
KW  - Alzheimer's disease
KW  -  Drosophila
KW  -  amyloid-beta (AB)
KW  -  animal model
KW  -  circadian rhythm
KW  -  fibril
KW  -  neurodegenerative disease
KW  -  oligomer
KW  -  prion
KW  -  protein misfolding
KW  -  Alzheimer Disease
KW  -  Amyloid
KW  -  Amyloid beta-Peptides
KW  -  Animals
KW  -  Circadian Rhythm
KW  -  Disease Models
KW  -  Animal
KW  -  Drosophila melanogaster
KW  -  Longevity
KW  -  Mesocricetus
KW  -  Neurotoxicity Syndromes
KW  -  Prion Proteins
KW  -  Protein Binding
KW  -  Protein Multimerization
ID  - discovery10073714
N2  - The cellular prion protein (PrPC) can act as a cell-surface receptor for ?-amyloid (A?) peptide; however, a role for PrPC in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of A? isoforms and PrPC in the Drosophila brain. We found that co-expression of A? and PrPC significantly reduces the lifespan, disrupts circadian rhythms, and increases A? deposition in the fly brain. In contrast, under the same conditions, expression of A? or PrPC individually did not lead to these phenotypic changes. In vitro studies revealed that substoichiometric amounts of PrPC trap A? as oligomeric assemblies and fragment-preformed A? fibers. The ability of membrane-anchored PrPC to trap A? as cytotoxic oligomers at the membrane surface and fragment inert A? fibers suggests a mechanism by which PrPC exacerbates A? 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 A? toxicity and supports a role for PrPC in AD pathogenesis. Blocking the interaction of A? and PrPC represents a potential therapeutic strategy.
TI  - Prion protein stabilizes amyloid-? (A?) oligomers and enhances A? neurotoxicity in a Drosophila model of Alzheimer's disease
EP  - 13099
Y1  - 2018/08/24/
AV  - public
JF  - Journal of Biological Chemistry
A1  - Younan, ND
A1  - Chen, K-F
A1  - Rose, R-S
A1  - Crowther, DC
A1  - Viles, JH
SN  - 1083-351X
UR  - https://doi.org/10.1074/jbc.RA118.003319
N1  - This version is the version of record. For information on re-use, please refer to the publisher?s terms and conditions.
IS  - 34
VL  - 293
SP  - 13090
ER  -