Freir, DB; Nicoll, AJ; Klyubin, I; Panico, S; Mc Donald, JM; Risse, E; Asante, EA; ... Collinge, J; + view all Freir, DB; Nicoll, AJ; Klyubin, I; Panico, S; Mc Donald, JM; Risse, E; Asante, EA; Farrow, MA; Sessions, RB; Saibil, HR; Clarke, AR; Rowan, MJ; Walsh, DM; Collinge, J; - view fewer (2011) Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites. Nature Communications , 2 , Article 336. 10.1038/ncomms1341.

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Preview	Other (JPG Figure 1: Biophysical characterization of Aβ species present in the bADDL preparation.) ncomms1341-f1.jpg Download (144kB)
Preview	Other (JPG Figure 2: PrPC is required for the inhibition of LTP by bADDLs and Aβ-containing extracts of human brain.) ncomms1341-f2.jpg Download (68kB)
Preview	Other (JPG Figure 3: bADDLs avidly bind PrP in a manner that can be blocked by certain anti-PrP antibodies.) ncomms1341-f3.jpg Download (93kB)
Preview	Other (JPG Figure 4: Inhibition of LTP by ADDLs or Aβ-containing AD brain extract is ameliorated by the anti-PrPC antibodies ICSM-35 and ICSM-18. ) ncomms1341-f4.jpg Download (145kB)
Preview	PDF (Supplementary Figures S1-S7, Supplementary Methods and Supplementary References.) ncomms1341-s1.pdf Download (1MB)

Abstract

A role for PrP in the toxic effect of oligomeric forms of A beta, 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 A beta-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/A beta-binding site and to PrP helix-1, were able to block A beta binding to PrP suggesting that the toxic A beta 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 A beta-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination.

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