title: Amyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity.
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 Aβ(1-42). 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 Aβ(1-42) 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.
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nicoll
authors.forename: Silvia
authors.initials: S
authors.lastname: Panico
authors.forename: Darragh B
authors.initials: DB
authors.lastname: Freir
authors.forename: Daniel
authors.initials: D
authors.lastname: Wright
authors.forename: Cassandra
authors.initials: C
authors.lastname: Terry
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Risse
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Herron
authors.forename: Tiernan
authors.initials: T
authors.lastname: O'Malley
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.forename: Mark A
authors.initials: MA
authors.lastname: Farrow
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Helen R
authors.initials: HR
authors.lastname: Saibil
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043942:Nanotubes / Q000633:toxicity*; D011328:Prions / Q000633:toxicity*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors; D014054:Tomography
chemical_list: D016229:Amyloid beta-Peptides; D011328:Prions
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