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bioRxiv · 10.64898/2026.04.19.719088

CXCL10 drives female-specific tau pathology progression and defines sex-dependent vulnerability in tauopathy model mice

Uenishi, R.·Kawata, R.·Manabe, T.·Matsuba, Y.·Mihira, N.·Takeo, T.·Sado, T. C.·Hijioka, M.·Saito, T.
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Abstract

Neuroinflammation is a central driver of tauopathy, yet the precise chemokines that orchestrate the inflammatory microenvironment remain elusive. Here, we report C-X-C motif chemokine ligand 10 (CXCL10) is markedly upregulated in the brains of tauopathy model mice, where it co-localizes with prominent tau pathology. Notably, genetic ablation of Cxcl10 in these mice significantly attenuates tau burden and extends the survival period, specifically in a female-dependent manner. Mechanistically, although Cxcl10 deficiency reduces the number of brain T cells in both sexes, this reduction does not correlate with the female-specific rescue of the phenotype. Furthermore, Cxcl10 deficiency did not alter glial cell activation or motor function, suggesting a sex-specific mechanism. We show CXCL10 is primarily produced by pathological glia, fostering a localized inflammatory microenvironment. Our findings identify CXCL10 as a key mediator of tau pathology and reveal a sex-dimorphic regulatory axis that operates independently of T cell and glial activation paradigms.

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Uenishi, R., Kawata, R., Manabe, T., Matsuba, Y., Mihira, N., Takeo, T., Sado, T. C., Hijioka, M., Saito, T.. 2026-04-22. CXCL10 drives female-specific tau pathology progression and defines sex-dependent vulnerability in tauopathy model mice. https://doi.org/10.64898/2026.04.19.719088

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