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Whether these interventions affect the actions of synaptotoxic, extracellular tau species that may contribute to cognitive impairment is relatively unknown. Here, we assayed synaptic plasticity disruption in anaesthetised live rats caused by intracerebral injection of synaptotoxic tau present either in (a) secretomes of induced pluripotent stem cell-derived neurons (iNs) from people with Trisomy 21, the most common genetic cause of AD, or (b) aqueous extracts of human AD brain. Extracellular tau in iN secretomes was found to include fragments that contain the extended microtubule-binding regions of tau, MTBR\/R\u2019 and adjacent C-terminal sequences. Immunodepletion or co-injection with antibodies targeting epitopes within these fragments prevented the acute disruption of synaptic plasticity by these patient-derived synaptotoxic tau preparations. Moreover, a recombinant human tau fragment encompassing the core MTBR\/R\u2019-region present in tau fibrils, tau\n                    <jats:sub>297-391<\/jats:sub>\n                    , potently mimicked the deleterious action of patient-derived tau. MTBR\/R\u2019-directed antibodies also rapidly reversed a very persistent synaptotoxic effect of soluble brain tau. Our findings reveal a hitherto relatively unexplored potential benefit of targeting extracellular MTBR\/R\u2019 tau on correcting synaptic dysfunction.\n                  <\/jats:p>","DOI":"10.1007\/s00401-025-02897-0","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T08:15:41Z","timestamp":1748852141000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region"],"prefix":"10.1007","volume":"149","author":[{"given":"Tomas","family":"Ondrejcak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng-Wei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Coode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant T.","family":"Corbett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Doykov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic M.","family":"Walsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick J.","family":"Livesey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Rowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Klyubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"2897_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.09.013","author":"E Barini","year":"2022","unstructured":"Barini E, Plotzky G, Mordashova Y, Hoppe J, Rodriguez-Correa E, Julier S et al (2022) Tau in the brain interstitial fluid is fragmented and seeding-competent. 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FJL is a founder and shareholder in Gen2 Neuroscience. D.M.W. is a former employee of and holds stock in Biogen, and he is also an advisor to Acumen, Apellis, BrainQr, Convergen and the Dementia Discovery Fund. The other authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Human brain tissue was used in accordance with Trinity College Dublin Faculty of Health Science Ethics Committee (approval 16014) and Partners Institutional Review Board (protocol, Walsh BWH 2011) guidelines. This research was carried out in accordance with the UK Code of Practice for the Use of Human Stem Cell Lines. 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