C-X-C Motif Chemokine 10/C-X-C Motif Chemokine Receptor 3 Signaling Induces Neural Senescence and Cognitive Impairments

Chemokine receptors belong to the G-protein-coupled receptor family, and emerging evidence suggests that chemokines are involved in central nervous system (CNS) aging. An increased level of CXCL10 in the CNS is reported in several neurodegenerative diseases, including Alzheimer's disease and virus-associated dementia. We also observed significantly increased expression of CXCL10 and CXCR3 in the prefrontal cortex and hippocampus of aged C57BL/6J mice (12 and 18 month old mice). This leads us to hypothesize that CXCL10, being a component of the senescence-associated secretory phenotype, may aggravate/perpetuate the brain aging process and, finally, neurodegenerative diseases. To test this hypothesis, we administered CXCL10 (intracerebroventricular: ICV, 0.5 pg/h, 28 days) in 8-month-old C57BL/6J mice. We observed increased expression of senescent marker proteins p16^INK4a, p21^Cip1, and p53 and decreased expression of pRB in the prefrontal cortex, which was blocked by CXCR3-specific antagonist AMG487. Furthermore, chronic infusion of CXCL10 induced learning and memory deficits in the Y-maze, social recognition, contextual freeze tests, and c-FOS expression in the prefrontal cortex. To further determine the specificity of CXCL10/CXCR3 signaling, we treated the primary cortical neuron (days <i>in vitro</i>: DIV-7-8) with CXCL10 and found increased senescence in a CXCR3-dependent fashion. Using RFP-EGFP-LC3-tagged transgenic mice, we also demonstrated that CXCL10/CXCR3 signaling attenuates autophagy in primary cortical neurons. Lastly, using a c-FOS-iRFP reporter, we observed that increased CXCL10/CXCR3 signaling impairs glutamate signaling in primary cortical neurons. These results support the hypothesis that increased CXCL10/CXCR3 signaling in neurons exacerbates brain aging and could be targeted for the management of aging-associated CNS disorders.