Down syndrome (Trisomy 21, Ts21) is the most common cause of early onset Alzheimer’s disease. We previously reported that secretomes of induced pluripotent stem cell (iPSC)-derived human Ts21 cortical neurons inhibited hippocampal long-term potentiation (LTP) in a tau-dependent manner (Hu et al., Cell Reports, 2018). Here, we employed electrophysiological recording from the CA1 area of the hippocampus of live rats under urethane anaesthesia to assess the ability of anti-tau antibodies to immunodeplete Ts21 iPSC-derived neuron synaptotoxic tau. We found that the mid-region (amino acids 210-241) monoclonal anti-tau antibody Tau5 prevented the inhibition of LTP by 200 Hz high-frequency stimulation (129±2%, n=6, p>0.05, compared with control LTP). In contrast, the monoclonal antibody Tau46 directed to the extreme C-terminus of tau (425-441) didn’t affect LTP inhibition (109±4%, n=10, p<0.05). Interestingly, unlike Tau46, immunodepletion with a polyclonal antibody targeting a much wider epitope of the C-terminus (243-441), K9JA, rescued LTP (147±6%, n=6, p>0.05). Taking into account experimental evidence of the role of tau aggregates in neuronal pathology, somewhat surprisingly, a monoclonal antibody raised against recombinant tau oligomers (TOMA-1) didn’t prevent inhibition of LTP (104±3%, p<0.05, n=4). Our results support further investigation of antibody-mediated tau targeting in various neurogenerative conditions. This work was supported by Science Foundation Ireland (19/FFP/6437) to M.J.R.