Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

Automated summary

This study revealed dysregulation of cerebrospinal fluid immune system during healthy brain aging and cognitive impairment. Age-related upregulation of lipid transport genes in monocytes and altered cytokine signaling to CD8 T cells were observed in cognitively normal subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred alongside the upregulation of CXCR6 in CD8 T cells and elevated expression of CXCL16 in the CSF, indicating a potential mechanism for antigen-specific T cell entry into the brain.