Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers

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Abstract
The hypothesis that soluble amyloid-β peptide oligomer plays a central role in Alzheimer's disease is well established, yet no mechanistic basis for Aβ oligomer effects on neurons has been described. Several lines of evidence point to the existence of a high-affinity cell-surface receptor for soluble Aβ oligomers on neurons as central to Alzheimer's disease pathology and now cellular prion protein PrPC has been identified as a candidate for that role. PrP, a plasma membrane glycoprotein associated with lipid rafts, binds Aβ oligomers selectively with high affinity and mediates the deleterious effects of the peptide. These data raise the possibility that PrPC-specific drugs might have therapeutic potential in Alzheimer's, and point to an unexpected link between infectious prion diseases and Alzheimer's disease. This paper shows that the effects of amyloid-beta oligomers on long-term potentiation are mediated by the cellular prion protein — notorious for its involvement in diseases such as bovine spongiform encephalopathy, new variant Creutzfeldt–Jakob disease and kuru. 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-β 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-β 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-β 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.