Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrPC), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβin vitrois controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampusin vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrPC, prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrPC, a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrPCin mediating synaptic plasticity disruption by soluble Aβ.