Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage
Name
jem_20221929.pdf
Description
Published version
Size
3.96 MB
Format
Adobe PDF
Checksum (MD5)
7e2b4dc3624c69394ae96ef52cef7ab0
Author(s)
Rustenhoven, Justin
Pavlou, Georgios
Storck, Steffen E
Dykstra, Taitea
Du, Siling
Wan, Zhengpeng
Quintero, Daniel
Scallan, Joshua P
Smirnov, Igor
Kamm, Roger D
Date Issued
July 3, 2023
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
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; Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage. J Exp Med 3 July 2023; 220 (7): e20221929.
Version
Final published version
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.
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DOI of Published Version
https://doi.org/10.1084/jem.20221929
