Amyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity

Andrew J. Nicoll, Silvia Panico, Darragh B. Freir, Daniel Wright, Cassandra Terry, Emmanuel Risse, Caroline E. Herron, Tiernan O’Malley, Jonathan D. F. Wadsworth, Mark A. Farrow, Dominic M. Walsh, Helen R. Saibil () and John Collinge ()
Additional contact information
Andrew J. Nicoll: UCL Institute of Neurology
Silvia Panico: Crystallography, Institute of Structural and Molecular Biology, Birkbeck College
Darragh B. Freir: UCL Institute of Neurology
Daniel Wright: UCL Institute of Neurology
Cassandra Terry: UCL Institute of Neurology
Emmanuel Risse: UCL Institute of Neurology
Caroline E. Herron: Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin
Tiernan O’Malley: Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin
Jonathan D. F. Wadsworth: UCL Institute of Neurology
Mark A. Farrow: UCL Institute of Neurology
Dominic M. Walsh: Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women’s Hospital, Harvard Institute of Medicine
Helen R. Saibil: Crystallography, Institute of Structural and Molecular Biology, Birkbeck College
John Collinge: UCL Institute of Neurology

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3416

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