The study identifies the cellular prion protein (PrP^C) as a receptor for amyloid-beta (Aβ) oligomers, which are implicated in Alzheimer's disease (AD) pathology. Aβ oligomers, which are toxic and can impair synaptic plasticity, bind to PrP^C with nanomolar affinity. This interaction does not require the infectious PrP^Sc conformation. In PrP null mice, the Aβ oligomer-induced blockade of long-term potentiation (LTP) is absent, indicating that PrP^C is essential for this synaptic dysfunction. Anti-PrP antibodies prevent Aβ oligomer binding to PrP^C and rescue synaptic plasticity in hippocampal slices. These findings suggest that PrP^C is a mediator of Aβ oligomer-induced synaptic dysfunction and that PrP^C-specific pharmaceuticals may have therapeutic potential for AD. The study also characterizes Aβ oligomer binding sites, showing that they are enriched in postsynaptic densities and bind to PrP^C-expressing cells. PrP^C is a high-affinity receptor for Aβ oligomers, with a dissociation constant (Kd) of approximately 50-100 nM. The binding is specific to Aβ oligomers and not to fresh Aβ42, indicating a high selectivity for the oligomeric form. PrP^C is expressed in hippocampal neurons and is localized to dendrites, where Aβ oligomers bind. The binding is saturable and is mediated by specific regions of PrP^C, particularly the 95–105 segment. The study further demonstrates that PrP^C is required for Aβ oligomer inhibition of LTP in wild-type mice, but not in PrP null mice. This suggests that PrP^C acts as a receptor for Aβ oligomers, mediating their inhibitory effects on synaptic plasticity. The findings support the hypothesis that PrP^C is a key mediator of Aβ oligomer-induced synaptic dysfunction in AD. The study also highlights the potential of PrP^C-specific reagents as molecular tools to understand the cellular basis of Aβ oligomer-induced changes in synaptic function. The interaction between Aβ and PrP^C provides a novel site for the development of therapeutics designed to relieve AD symptoms.The study identifies the cellular prion protein (PrP^C) as a receptor for amyloid-beta (Aβ) oligomers, which are implicated in Alzheimer's disease (AD) pathology. Aβ oligomers, which are toxic and can impair synaptic plasticity, bind to PrP^C with nanomolar affinity. This interaction does not require the infectious PrP^Sc conformation. In PrP null mice, the Aβ oligomer-induced blockade of long-term potentiation (LTP) is absent, indicating that PrP^C is essential for this synaptic dysfunction. Anti-PrP antibodies prevent Aβ oligomer binding to PrP^C and rescue synaptic plasticity in hippocampal slices. These findings suggest that PrP^C is a mediator of Aβ oligomer-induced synaptic dysfunction and that PrP^C-specific pharmaceuticals may have therapeutic potential for AD. The study also characterizes Aβ oligomer binding sites, showing that they are enriched in postsynaptic densities and bind to PrP^C-expressing cells. PrP^C is a high-affinity receptor for Aβ oligomers, with a dissociation constant (Kd) of approximately 50-100 nM. The binding is specific to Aβ oligomers and not to fresh Aβ42, indicating a high selectivity for the oligomeric form. PrP^C is expressed in hippocampal neurons and is localized to dendrites, where Aβ oligomers bind. The binding is saturable and is mediated by specific regions of PrP^C, particularly the 95–105 segment. The study further demonstrates that PrP^C is required for Aβ oligomer inhibition of LTP in wild-type mice, but not in PrP null mice. This suggests that PrP^C acts as a receptor for Aβ oligomers, mediating their inhibitory effects on synaptic plasticity. The findings support the hypothesis that PrP^C is a key mediator of Aβ oligomer-induced synaptic dysfunction in AD. The study also highlights the potential of PrP^C-specific reagents as molecular tools to understand the cellular basis of Aβ oligomer-induced changes in synaptic function. The interaction between Aβ and PrP^C provides a novel site for the development of therapeutics designed to relieve AD symptoms.