The study identifies the cellular Prion Protein (PrpC) as a receptor for amyloid-β (Aβ) oligomers, which are early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ-oligomers bind to PrpC with nanomolar affinity, and this interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult Prnp null mice is normal, but the Aβ-oligomer blockade of long-term potentiation (LTP) is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrpC and rescue LTP in hippocampal slices from Prnp null mice. These findings suggest that PrpC is a mediator of Aβ-oligomer-induced synaptic dysfunction, and PrpC-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease. The study also characterizes the binding sites of Aβ-oligomers and demonstrates that PrpC is essential for Aβ-oligomer inhibition of hippocampal LTP.The study identifies the cellular Prion Protein (PrpC) as a receptor for amyloid-β (Aβ) oligomers, which are early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ-oligomers bind to PrpC with nanomolar affinity, and this interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult Prnp null mice is normal, but the Aβ-oligomer blockade of long-term potentiation (LTP) is absent. Anti-PrP antibodies prevent Aβ-oligomer binding to PrpC and rescue LTP in hippocampal slices from Prnp null mice. These findings suggest that PrpC is a mediator of Aβ-oligomer-induced synaptic dysfunction, and PrpC-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease. The study also characterizes the binding sites of Aβ-oligomers and demonstrates that PrpC is essential for Aβ-oligomer inhibition of hippocampal LTP.