Nature 457, 1128-1132 (26 February 2009) | doi:10.1038/nature07761
Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Juha Laurén1, David A. Gimbel1, Haakon B. Nygaard1, John W. Gilbert1 & Stephen M. Strittmatter1
Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA
Correspondence to: Stephen M. Strittmatter1 Correspondence and requests for materials should be addressed to S.M.S.
A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40�42 amino acid residues1. Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction2, 3, 4, 5, 6, 7, 8, 9. At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5, 8 and impair rodent spatial memory2. Soluble amyloid- oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain2, 4, 7, 9. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid- oligomers on neurons―one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrPc) as an amyloid-β-oligomer receptor by expression cloning. Amyloid- oligomers bind with nanomolar affinity to PrPc, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrPc and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrPc is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrPc-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.
