Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis

Kauwe, G.; Lokitiyakul, D.; Wong, I. L.; Schneider, K.; Sridhar, V.; Sellegounder, D.; Ngwala, Y. Y.; Yao, L.; Chen, J. H.; Pareja-Navarro, K. A.; Nana, A. L.; Spina, S.; Seeley, W. W.; Grinberg, L. T.; Verdin, E.; Furman, D.; Karch, C. M.; Gan, L.; Tracy, T. E.

doi:10.1101/2025.09.11.675671

bioRxiv · 10.1101/2025.09.11.675671

Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis

Kauwe, G.·Lokitiyakul, D.·Wong, I. L.·Schneider, K.·Sridhar, V.·Sellegounder, D.·Ngwala, Y. Y.·Yao, L.·Chen, J. H.·Pareja-Navarro, K. A.·Nana, A. L.·Spina, S.·Seeley, W. W.·Grinberg, L. T.·Verdin, E.·Furman, D.·Karch, C. M.·Gan, L.·Tracy, T. E.

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Abstract

Activity-dependent modulation of synaptic strength is critical for encoding memories and it is inhibited in tauopathies including Alzheimers disease (AD) and Frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Pathogenic tau accumulates in neurons where it obstructs synaptic plasticity. How tau blocks synaptic plasticity leading to memory loss is unclear. Here, we show that FTLD-tau inhibits plasticity by blocking activity-dependent protein synthesis in dendrites. In the plasticity-associated translatome, we identified a subset of downregulated translated mRNAs in FTLD-tau neurons that encode postsynaptic plasticity regulators. Protein synthesis was blocked by FTLD-tau binding to eIF4B which caused eIF4B dissociation from the translation initiation complex and reduced dendritic eIF4B levels. Inhibiting the tau-eIF4B interaction or enhancing eIF4B levels in FTLD-tau neurons restored local protein synthesis and synaptic plasticity. Together, this suggests that pathogenic tau binding to eIF4B disables the local synthesis of plasticity-related proteins that drive synapse strengthening and memory formation.

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Kauwe, G., Lokitiyakul, D., Wong, I. L., Schneider, K., Sridhar, V., Sellegounder, D., Ngwala, Y. Y., Yao, L., Chen, J. H., Pareja-Navarro, K. A., Nana, A. L., Spina, S., Seeley, W. W., Grinberg, L. T., Verdin, E., Furman, D., Karch, C. M., Gan, L., Tracy, T. E.. 2025-09-12. Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis. https://doi.org/10.1101/2025.09.11.675671

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