The interaction of amyloid-beta and microtubule-associated protein tau, the two hallmark proteins of Alzheimer’s disease (AD) age-related pathology, that cause disruption of synaptic long-term potentiation and depression (LTP and LTD, respectively) is still poorly understood. Here, we recorded field excitatory postsynaptic potentials from the CA1 stratum radiatum in young and middle-aged rats under urethane anesthesia to examine the disruptive action of synaptotoxic tau in recombinant protein preparations or aqueous brain extracts from patients with AD and Pick’s disease (PiD) tauopathy. A single intracerebral injection of soluble aggregates of recombinant human tau that had been prepared by disulfide bond-induced oligomerization (oTau), sonication of fibrils (soluble tau aggregates, SτAs), or tau-containing patient brain extracts rapidly disrupted synaptic plasticity in rat hippocampus. Specifically, recombinant oTau acutely facilitated hippocampal LTD in an age-dependent manner, and inhibited LTP. The disruption of plasticity was prevented by a conformational monoclonal antibody (TOMA-1) that targets tau oligomers, and by an agent, etanercept, that neutralizes the pro-inflammatory cytokine TNFα. In contrast, SτAs potently inhibited synaptic LTD, an effect not prevented by etanercept. Unlike epitope-specific antibody against tau (Tau5), co-injection of the same dose of TOMA-1 did not prevent acute plasticity-disrupting effects of patient-derived brain tau. We conclude that tau aggregates prepared from different sources that differ in size and conformation can have opposing effects on synaptic plasticity. Furthermore, recombinant and patient-derived tau species can disrupt plasticity via different downstream mediators and with a differential sensitivity to certain tau antibodies.