The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits

Silva, J. M.; Lahiri, S. M.; Monteiro-Fernandes, D.; Soares-Cunha, C.; Solis-Mezarino, V.; Volker-Alber, M.; Gomes, P.; Campos-Marques, C.; Coimbra, B.; Campos, I. C.; Samiotaki, M.; Panayotou, G.; Kokras, N.; Dalla, C.; Wolozin, B.; Oliveira, J.; Abisambra, J.; Imhof, A.; Rodrigues, A. J.; Sousa, N.; Sotiropoulos, I.

doi:10.64898/2026.01.21.700784

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bioRxiv · 10.64898/2026.01.21.700784

The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits

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Abstract

INTRODUCTIONAccumulation of pathological Tau precipitates neuronal malfunction in Alzheimers disease (AD). However, the impact of loss of normal Tau function in the adult brain, independently of Tau aggregates, remains unclarified. METHODSWe used a mouse model with conditional mapt knocking-down in forebrain of 5-7 months old animals (cTau-KO), a virus-driven selective Tau knockdown in wild-types (WT) and Tau re-expression approaches, accompanied by neurostructural, epigenetic, proteomic, electrophysiological, neurochemical and behavioral analyses. RESULTSLoss of Tau in the adult brain of cTau-KOs triggers neuronal atrophy and malfunction, epigenetic as well cognitive and mood deficits. Importantly, these perturbations were confirmed by selective Tau loss in WT adult brain and reverted by Tau re-expression or pharmacologically-induced epigenetic correction in cTau-KOs. DISCUSSIONOur findings highlight the contribution of loss of normal Tau function in the adult brain malfunction that could be relevant in diverse brain pathologies beyond AD, associated to Tau and its dysfunction.

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Silva, J. M., Lahiri, S. M., Monteiro-Fernandes, D., Soares-Cunha, C., Solis-Mezarino, V., Volker-Alber, M., Gomes, P., Campos-Marques, C., Coimbra, B., Campos, I. C., Samiotaki, M., Panayotou, G., Kokras, N., Dalla, C., Wolozin, B., Oliveira, J., Abisambra, J., Imhof, A., Rodrigues, A. J., Sousa, N., Sotiropoulos, I.. 2026-01-23. The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits. https://doi.org/10.64898/2026.01.21.700784

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