This is a summary of Groh, J., Feng, R., Yuan et al. et al. ‘Microglia activation orchestrates CXCL10-mediated CD8+T cell recruitment to promote aging-related white matter degeneration’ published in Nature Neuroscience (2025). https://doi.org/10.1038/s41593-025-01955-w
The challenge
Aging is the primary risk factor for neurodegeneration. The white matter of the brain, which is mainly composed of myelinated axons, is especially susceptible to aging-related changes. As we age, white matter decreases in volume, loses its microstructural properties, and develops areas of damage. This includes the formation of fragmented and redundant myelin, as well as damage and degeneration of axons. The precise mechanisms and their impact on aging white matter are not completely understood. Therefore, in this study, we focused on one of these processes – investigating the role of microglia in aging-associated changes of myelinated axons.
Our approach
We used pharmacological and genetic approaches in aging mice to target distinct populations of glial cells and their interaction with peripheral immune cells. We characterized glial heterogeneity and aging-related changes in white matter using single-cell and spatial transcriptomics (incl. MERFISH). By integrating traditional neurobiological and immunological techniques with high-resolution gene expression analysis, we investigated the mechanisms of how aging may result in white matter decline in mice and humans.
Our findings
We found elaborate interactions between support cells and immune cells – glial-immune interactions – in the aging white matter. Notably, we found that the chronic activation of microglia becomes maladaptive and damaging instead of helpful and leads to the accumulation of harmful cytotoxic CD8+ T cells. As a result, myelinated axons degenerate leading to a loss of brain function. In particular, we found that CXCL10, an interferon-stimulated chemokine for CXCR3+ cells, is crucial in this process: it recruits and retains the CD8+ T cells. We propose that aging-related damage of oligodendrocytes and myelin and the subsequent reactivity of microglia provoke a response from astrocytes, leading to elevated CXCL10 levels and the accumulation of CD8+ T cells in white matter.
The implications
Interactions between reactive glia and their upregulation of CXCL10 are common features in various neurological disorders and aging and are associated with increased numbers of CD8+ CXCR3+ tissue resident memory T cells. Targeting the recruitment or retention of these CD8+ T cells could be a promising treatment approach for maladaptive immune responses in aging, neuroinflammatory, and neurodegenerative diseases.
Creating SyNergies
The study was led by our Spatial Transcriptomics Hub Leader Janos Groh and our member Mikael Simons and the team included SyNergy member Jonas Neher. The researchers closely collaborated with the group of Rudolf Martini from the University of Würzburg. By leveraging expertise in glial biology and neuroimmunology across multiple groups, the team synergized hypothesis-driven and unbiased approaches to identify targetable pathways involved in aging-related neurodegeneration. Future projects within SyNergy will build upon these findings, exploring their implications for age-associated diseases and their potential translational relevance.
