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

    Freir, D.B. and Nicoll, A.J. and Klyubin, I. and Panico, Silvia and McDonald, J.M. and Risse, E. and Asante, E.A. and Farrow, M.A. and Sessions, R.B. and Saibil, Helen R. and Clarke, A.R. and Rowan, M.J. and Walsh, D.M. and Collinge, J. (2011) Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nature Communications 2 , ISSN 2041-1723.

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    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.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): Biological Sciences, Biochemistry, Biophysics, Neuroscience
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 20 Apr 2012 09:39
    Last Modified: 06 Dec 2016 11:14
    URI: http://eprints.bbk.ac.uk/id/eprint/4719

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