Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage

The meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer's disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age-related dysfunction represents a promising strategy to augment CNS waste clearance; however, the mechanisms underlying this decline remain elusive. Here, we demonstrate that age-related alterations in meningeal immunity underlie this lymphatic impairment. Single-cell RNA sequencing of meningeal lymphatic endothelial cells from aged mice revealed their response to IFN gamma, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFN gamma in young mice via AAV-mediated overexpression attenuated CSF drainage-comparable to the deficits observed in aged mice. Therapeutically, IFN gamma neutralization alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal. Impaired lymphatic drainage of brain waste occurs in aging and disease, but the cause remains elusive. Here, Rustenhoven et al. describe how meningeal immune cell-derived IFN gamma underlies this age-related deficit and demonstrate its therapeutic manipulation to improve waste clearance.