%0 Journal Article
%A Groh, Janos
%A Feng, Ruoqing
%A Yuan, Xidi
%A Liu, Lu
%A Klein, Dennis
%A Hutahaean, Gladis
%A Butz, Elisabeth
%A Wang, Zhen
%A Steinbrecher, Lisa
%A Neher, Jonas
%A Martini, Rudolf
%A Simons, Mikael
%T Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
%J Nature neuroscience
%V 28
%N 6
%@ 1097-6256
%C New York, NY
%I Nature America
%M DZNE-2025-00681
%P 1160 - 1173
%D 2025
%X Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.
%K Animals
%K Microglia: immunology
%K Microglia: metabolism
%K White Matter: pathology
%K White Matter: immunology
%K White Matter: metabolism
%K CD8-Positive T-Lymphocytes: immunology
%K CD8-Positive T-Lymphocytes: metabolism
%K Mice
%K Aging: pathology
%K Aging: immunology
%K Chemokine CXCL10: metabolism
%K Chemokine CXCL10: immunology
%K Mice, Inbred C57BL
%K Receptors, CXCR3: metabolism
%K Myelin Sheath
%K Male
%K Mice, Transgenic
%K Nerve Degeneration: pathology
%K Nerve Degeneration: immunology
%K Chemokine CXCL10 (NLM Chemicals)
%K Receptors, CXCR3 (NLM Chemicals)
%K Cxcl10 protein, mouse (NLM Chemicals)
%K Cxcr3 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40404995
%R 10.1038/s41593-025-01955-w
%U https://pub.dzne.de/record/279051