Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition and amyloid beta pathology

Aging leads to a progressive deterioration in brain function, which will eventually result in cognitive decline and can develop into a dementia. The mechanisms underlying pathological cognitive decline in aging are still poorly understood. The peripheral immune system, as well as the meningeal lymphatic vasculature and the immune cells residing in the brain and meninges, are all affected by aging. Moreover, recent studies have linked the dysfunction of the meningeal lymphatic system and peripheral immunity to accelerated brain aging. We hypothesized that an age-related reduction in CCR7-dependent immune cell egress through the lymphatic vasculature mediates some aspects of aging-associated brain dysfunction, leading to cognitive decline and potentially exacerbating neurodegenerative diseases. Here, we report a reduction in CCR7 expression by meningeal T cells in aged mice and its associated increase in meningeal T-regulatory cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to cognitive impairment. Interestingly, CCR7-deficient mice also presented impaired brain glymphatic function and showed increased amyloid beta (A?) deposition when crossed with the 5xFAD transgenic mouse model of Alzheimer's disease (AD). These results show that the aging-associated decrease in CCR7 expression impacts meningeal immunity, affects different aspects of brain function and exacerbates brain A? pathology, highlighting its potential as a pathogenic mechanism for cognitive decline in aging and AD. Overall design: Brain cells were isolated from 5 months old male 5xFAD mice, deficient for CCR7 (5xFAD::CCR7-/-, n=3) or age-matched control littermates (5xFAD, n=3). Brain cell suspensions were obtained by enzymatic and mechanic digestion of right brain hemisphere tissue, stained for surface markers and enriched for specific populations (microglia/macrophages - live CD45+CD11b+Ly6G–, and blood endothelial cells - live CD45–CD11b–CD13–CD31+) by FACS sorting. Each individual sample used in this single-cell RNA sequencing experiment resulted from brain cells pooled from 3 mice.