Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region

Ondrejcak, T.; Hu, N.-W.; Coode, E.; Campbell, T.; Corbett, G. T.; Doykov, I.; Mills, K.; Walsh, D. M.; Livesey, F. J.; Rowan, M. J.; Klyubin, I.

doi:10.1101/2025.02.21.639417

bioRxiv · 10.1101/2025.02.21.639417

Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region

Ondrejcak, T.·Hu, N.-W.·Coode, E.·Campbell, T.·Corbett, G. T.·Doykov, I.·Mills, K.·Walsh, D. M.·Livesey, F. J.·Rowan, M. J.·Klyubin, I.

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Abstract

Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimers disease (AD) will slow dementia pathogenesis. How these interventions affect the actions of synaptotoxic, extracellular tau species that may help mediate 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 and adjacent C-terminal peptides. 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. Conversely, a recombinant human tau fragment encompassing the core MTBR/R- region present in tau fibrils, tau297-391 potently mimicked this deleterious action of patient-derived tau. MTBR/R-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 MTBR/R.

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Ondrejcak, T., Hu, N.-W., Coode, E., Campbell, T., Corbett, G. T., Doykov, I., Mills, K., Walsh, D. M., Livesey, F. J., Rowan, M. J., Klyubin, I.. 2025-02-24. Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region. https://doi.org/10.1101/2025.02.21.639417

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