Journal
NATURE COMMUNICATIONS
Volume 2, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1341
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Funding
- Science Foundation Ireland [08/1N.1/B2033, 06/IN.1/B88]
- Health Research Board [RP/2008/30]
- UCD [SF339]
- United Kingdom Medical Research Council
- Department of Health (England)
- Science Foundation Ireland (SFI) [06/IN.1/B88] Funding Source: Science Foundation Ireland (SFI)
- MRC [MC_U123160653, MC_U123160656, MC_U123192748] Funding Source: UKRI
- Health Research Board (HRB) [RP-2008-30] Funding Source: Health Research Board (HRB)
- Medical Research Council [MC_U123160653, MC_U123160656, MC_U123192748] Funding Source: researchfish
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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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