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Deposition of abnormally phosphorylated tau aggregates is a central event leading to neuronal dysfunction and death in Alzheimer's disease (AD) and other tauopathies. Among tau aggregates, oligomers (TauOs) are considered the most toxic. AD brains show significant increase in TauOs compared to healthy controls, their concentration correlating with the severity of cognitive deficits and disease progression. In vitro and in vivo neuronal TauO exposure leads to synaptic and cognitive dysfunction, but their mechanisms of action are unclear. Evidence suggests that the cellular prion protein (PrP C ) may act as a mediator of TauO neurotoxicity, as previously proposed for β-amyloid and α-synuclein oligomers. To investigate whether PrP C mediates TauO detrimental activities, we compared their effects on memory and synaptic plasticity in wild type (WT) and PrP C knockout (Prnp 0/0 ) mice. Intracerebroventricular injection of TauOs significantly impaired recognition memory in WT but not in Prnp 0/0 mice. Similarly, TauOs inhibited long-term potentiation in acute hippocampal slices from WT but not Prnp 0/0 mice. Surface plasmon resonance indicated a high-affinity binding between TauOs and PrP C with a K D of 20-50 nM. Immunofluorescence analysis of naïve and PrP C -overexpressing HEK293 cells exposed to TauOs showed a PrP C dose-dependent association of TauOs with cells over time, and their co-localization with PrP C on the plasma membrane and in intracellular compartments, suggesting PrP C -may play a role in TauO internalization. These findings support the concept that PrP C mediates the detrimental activities of TauOs through a direct interaction, suggesting that targeting this interaction might be a promising therapeutic strategy for AD and other tauopathies., Competing Interests: Declarations. Ethics approval and consent to participate: The Mario Negri Institute for Pharmacological Research adheres to the principles set out in the following laws, regulation, and policies governing the Care and Use of Laboratory Animals: Italian Governing Law (D.lgs 26/2014; Authorization N°19/2008-A issued March 6, 2008 by Ministry of Health); Mario Negri Institutional Regulations and Policies providing internal authorization for persons conducting animal experiments (Quality Management System Certificate – UNI EN ISO 9001:2015 – Reg. N° 6121); the NIH Guide for the Care and Use of Laboratory Animals (2011 edition) and EU directives and guidelines (EEC Council Directive 2010/63/UE). The statement of Compliance (Assurance) with the Public Health Service (PHS) Policy on Human Care and Use of Laboratory Animals was reviewed on 9/9/2014 (Animal Welfare Assurance #A5023-01). All animals were managed in accordance with European directive 2010/63/UE and with Italian law D.l. 26/2014. The procedures were approved by the local animal-health and ethical committee and were authorized by the national authority (Istituto Superiore di Sanità; authorization numbers 370/2016-PR and 532/2021-PR). All efforts were made to reduce the number of animals by following the 3R’s rule. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)