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 -