Nicoll, AJ; Panico, S; Freir, DB; Wright, D; Terry, C; Risse, E; Herron, CE; ... Collinge, J; + view all Nicoll, AJ; Panico, S; Freir, DB; Wright, D; Terry, C; Risse, E; Herron, CE; O'Malley, T; Wadsworth, JD; Farrow, MA; Walsh, DM; Saibil, HR; Collinge, J; - view fewer (2013) Amyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity. Nature Communications , 4 , Article 2416 . 10.1038/ncomms3416.

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Abstract

Growing evidence suggests water-soluble, non-fibrillar forms of amyloid-β protein (Aβ) have important roles in Alzheimer's disease with toxicities mimicked by synthetic Aβ1-42. However, no defined toxic structures acting via specific receptors have been identified and roles of proposed receptors, such as prion protein (PrP), remain controversial. Here we quantify binding to PrP of Aβ1-42 after different durations of aggregation. We show PrP-binding and PrP-dependent inhibition of long-term potentiation (LTP) correlate with the presence of protofibrils. Globular oligomers bind less avidly to PrP and do not inhibit LTP, whereas fibrils inhibit LTP in a PrP-independent manner. That only certain transient Aβ assemblies cause PrP-dependent toxicity explains conflicting reports regarding the involvement of PrP in Aβ-induced impairments. We show that these protofibrils contain a defined nanotubular structure with a previously unidentified triple helical conformation. Blocking the formation of Aβ nanotubes or their interaction with PrP might have a role in treatment of Alzheimer's disease.

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