Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites

Darragh B. Freir, Andrew J. Nicoll, Igor Klyubin, Silvia Panico, Jessica M. Mc Donald, Emmanuel Risse, Emmanuel A. Asante, Mark A. Farrow, Richard B. Sessions, Helen R. Saibil, Anthony R. Clarke, Michael J. Rowan, Dominic M. Walsh () and John Collinge ()
Additional contact information
Darragh B. Freir: Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin
Andrew J. Nicoll: UCL Institute of Neurology, Queen Square, London WCN1 3BG, UK.
Igor Klyubin: Institute of Neuroscience, Biotechnology Building, Trinity College, Dublin 2, Republic of Ireland.
Silvia Panico: Institute of Structural and Molecular Biology, Birkbeck College
Jessica M. Mc Donald: Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin
Emmanuel Risse: UCL Institute of Neurology, Queen Square, London WCN1 3BG, UK.
Emmanuel A. Asante: UCL Institute of Neurology, Queen Square, London WCN1 3BG, UK.
Mark A. Farrow: UCL Institute of Neurology, Queen Square, London WCN1 3BG, UK.
Richard B. Sessions: School of Medical Sciences, University of Bristol
Helen R. Saibil: Institute of Structural and Molecular Biology, Birkbeck College
Anthony R. Clarke: UCL Institute of Neurology, Queen Square, London WCN1 3BG, UK.
Michael J. Rowan: Institute of Neuroscience, Biotechnology Building, Trinity College, Dublin 2, Republic of Ireland.
Dominic M. Walsh: Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin
John Collinge: UCL Institute of Neurology, Queen Square, London WCN1 3BG, UK.

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract A role for PrP in the toxic effect of oligomeric forms of Aβ, implicated in Alzheimer's disease (AD), has been suggested but remains controversial. Here we show that PrP is required for the plasticity-impairing effects of ex vivo material from human AD brain and that standardized Aβ-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP-dependent manner. We screened a panel of anti-PrP antibodies for their ability to disrupt the ADDL–PrP interaction. Antibodies directed to the principal PrP/Aβ-binding site and to PrP helix-1, were able to block Aβ binding to PrP suggesting that the toxic Aβ species are of relatively high molecular mass and/or may bind multiple PrP molecules. Two representative and extensively characterized monoclonal antibodies directed to these regions, ICSM-35 and ICSM-18, were shown to block the Aβ-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination.

Date: 2011
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DOI: 10.1038/ncomms1341

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