TY  - JOUR
AU  - Groh, Janos
AU  - Feng, Ruoqing
AU  - Yuan, Xidi
AU  - Liu, Lu
AU  - Klein, Dennis
AU  - Hutahaean, Gladis
AU  - Butz, Elisabeth
AU  - Wang, Zhen
AU  - Steinbrecher, Lisa
AU  - Neher, Jonas
AU  - Martini, Rudolf
AU  - Simons, Mikael
TI  - Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
JO  - Nature neuroscience
VL  - 28
IS  - 6
SN  - 1097-6256
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2025-00681
SP  - 1160 - 1173
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Microglia: immunology
KW  - Microglia: metabolism
KW  - White Matter: pathology
KW  - White Matter: immunology
KW  - White Matter: metabolism
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - CD8-Positive T-Lymphocytes: metabolism
KW  - Mice
KW  - Aging: pathology
KW  - Aging: immunology
KW  - Chemokine CXCL10: metabolism
KW  - Chemokine CXCL10: immunology
KW  - Mice, Inbred C57BL
KW  - Receptors, CXCR3: metabolism
KW  - Myelin Sheath
KW  - Male
KW  - Mice, Transgenic
KW  - Nerve Degeneration: pathology
KW  - Nerve Degeneration: immunology
KW  - Chemokine CXCL10 (NLM Chemicals)
KW  - Receptors, CXCR3 (NLM Chemicals)
KW  - Cxcl10 protein, mouse (NLM Chemicals)
KW  - Cxcr3 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40404995
DO  - DOI:10.1038/s41593-025-01955-w
UR  - https://pub.dzne.de/record/279051
ER  -