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

Justin Rustenhoven, Georgios Pavlou, Steffen E. Storck, Taitea Dykstra, Siling Du, Zhengpeng Wan, Daniel Quintero, Joshua P. Scallan, Igor Smirnov, Roger D. Kamm, Jonathan Kipnis

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 IFNγ, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFNγ in young mice via AAV-mediated overexpression attenuated CSF drainage—comparable to the deficits observed in aged mice. Therapeutically, IFNγ 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.

Original languageEnglish
Article numbere20221929
JournalJournal of Experimental Medicine
Volume220
Issue number7
DOIs
StatePublished - Jul 3 2023

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