Single-cell transcriptomic profiling reveals subset specific changes in brain T cells in an aged mouse model of chronic cerebral hypoperfusion

Vascular dementia is the second leading cause of cognitive impairment in the elderly, and chronic cerebral hypoperfusion (CCH) is a major contributing factor. Increasing evidence suggests that T cells play important roles in modulating neurodegeneration and cognitive function. However, the effects of CCH on brain-infiltrating T cells, particularly in the context of aging, remain poorly understood. Single-cell RNA sequencing, flow cytometry, and qPCR were used to characterize T cell populations in the brains of aged mice subjected to CCH. Cerebral blood flow, blood brain barrier (BBB) integrity, microglial inflammation, and cognitive function were assessed in aged mice subjected to CCH and treated with IL17a-neutralizing antibody or isotype control. CCH led to significant cognitive impairment in aged mice. In the aged brain, CCH induced subset-specific alterations in infiltrating T cells, including selective increases in γδ T cells, Th17 cells, regulatory T cells (Tregs), and proliferating T cells. Distinct transcriptional changes were observed across different T cell subsets, with minimal overlap in differentially expressed genes (DEGs) among subsets. Changes in T cell subset composition contributed substantially to the overall transcriptional alterations in brain T cells, with Il17a identified as the most significantly upregulated gene. Neutralization of IL17a ameliorated BBB leakage, reduced neuroinflammation and improved cognitive function in aged mice with CCH. This study reveals subset-specific alterations in brain-infiltrating T cells induced by CCH in aged mice and indicates that increased IL17a contributed to aging-associated vascular dementia.