CXCL10 contributes to female-specific pathological progression in tauopathy model mice.

Abstract

Neuroinflammation plays a central role in the progression of tauopathy via the glial activation and T cell accumulation in the brain parenchyma. However, the key molecular mediators that link these processes to tau pathology remain poorly understood.Here, we identify C-X-C motif chemokine ligand 10 (CXCL10) as a critical inflammatory mediator that is markedly upregulated in the brains of P301S-mutant tau transgenic mice and associated with regions of severe tau pathology. Spatial transcriptomics revealed that CXCL10 is mainly expressed by disease-associated astrocytes, defining an astrocytic CXCL10-rich inflammatory niche within the tauopathy brain.Genetic ablation of Cxcl10 significantly attenuated soluble and insoluble tau accumulation selectively in 9-month-old female mice, whereas no attenuation of tau accumulation was observed at 11-12 months of age. In addition, Cxcl10 deficiency significantly prolonged survival specifically in female tauopathy mice. Although Cxcl10 deficiency reduced the number of parenchymal T cells in both sexes, this reduction did not explain the female-specific effects. Furthermore, Cxcl10 deficiency did not alter neurodegeneration and motor dysfunction, suggesting that downstream sex-dependent regulatory mechanisms govern tauopathy progression. Moreover, CXCL10-dependent inflammatory activation within the local microenvironments was observed in both sexes. Although the molecular mechanisms underlying the sex-dependent effects of CXCL10 remain unclear, these findings suggest that CXCL10 contributes to tau pathology through multiple inflammatory pathways.In summary, our findings identify CXCL10 as a key inflammatory mediator of sex specific tau-associated pathology.