Whether blocking CXCR3 (via genetic deletion or systemic antibody treatment) could reduce T cell brain infiltration, neurodegeneration, and cognitive decline in a mouse model of tauopathy, using IFNγ-induced CXCL10 upregulation as a mechanistic trigger.
Chronic systemic anti-CXCR3 antibody treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition; it also decreased microglial MHC-II expression and shifted CD8+ T cells toward terminal exhaustion without broadly suppressing disease-associated microglial inflammatory phenotypes.
Findings are limited to a mouse model of tauopathy and may not directly translate to human disease; the specific tauopathy model used and long-term safety of peripheral CXCR3 blockade are not fully characterized in this abstract; mechanistic specificity of which T cell subtypes drive neurodegeneration remains partially defined.
CXCR3 blockade is not yet clinically available for tauopathies, but these preclinical data position peripheral anti-CXCR3 therapy as a candidate disease-modifying strategy worth investigating in early-phase human trials for tau-related neurodegeneration.
