title: Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites.
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.
authors.affiliation: Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Republic of Ireland.
authors.forename: Darragh B
authors.initials: DB
authors.lastname: Freir
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nicoll
authors.forename: Igor
authors.initials: I
authors.lastname: Klyubin
authors.forename: Silvia
authors.initials: S
authors.lastname: Panico
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mc Donald
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Risse
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Asante
authors.forename: Mark A
authors.initials: MA
authors.lastname: Farrow
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sessions
authors.forename: Helen R
authors.initials: HR
authors.lastname: Saibil
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Clarke
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D006801:Humans; D008024:Ligands; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008958:Models, Molecular; D009473:Neuronal Plasticity / Q000502:physiology*; D011328:Prions / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology*; D014461:Ultracentrifugation
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D008024:Ligands; D011328:Prions