Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites
| Autor: | Jessica M. Mc Donald, Darragh B. Freir, Dominic M. Walsh, Igor Klyubin, Emmanuel A. Asante, John Collinge, Silvia Panico, Andrew J. Nicoll, Richard B. Sessions, Helen R. Saibil, M Farrow, Michael J. Rowan, Anthony R. Clarke, Emmanuel Risse |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Prions medicine.drug_class animal diseases Long-Term Potentiation General Physics and Astronomy Biology Ligands Monoclonal antibody Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease In vivo medicine Animals Humans Binding site Chromatography High Pressure Liquid 030304 developmental biology Mice Knockout 0303 health sciences Amyloid beta-Peptides Neuronal Plasticity Multidisciplinary Antibodies Monoclonal Long-term potentiation General Chemistry medicine.disease nervous system diseases 3. Good health Electrophysiology Microscopy Electron Biochemistry Synapses Synaptic plasticity Monoclonal Chromatography Gel Electrophoresis Polyacrylamide Gel Alzheimer's disease Ultracentrifugation 030217 neurology & neurosurgery Ex vivo |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms1341 |
| Popis: | 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. The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins. |
| Databáze: | OpenAIRE |
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