New study seveals how microglia protect the aging spinal cord
Researchers affiliated to CMM have recently uncovered a key mechanism by which immune cells of the central nervous system help safeguard spinal cord integrity during aging. The study, published in Nature Neuroscience, shows that as mice age, the myelin sheaths in a specific spinal cord region—the dorsal columns—undergo significant ultrastructural decline. The researchers further found that microglia upregulate a signaling molecule called TGF-β in this region, acting as a “brake” that restrains overactivation and protects myelin from further damage. When TGF-β signaling was experimentally blocked in microglia in older mice, these cells became excessively activated and began attacking myelin in the dorsal column, leading to severe neurological dysfunction.
Based on these findings, the researchers proposed a theoretical framework for maintaining myelin health in the spinal dorsal column during aging. During normal aging, the long-term accumulation of myelin-associated changes triggers low-level activation and immune responses in dorsal column microglia. At this stage, microglia adapt protectively by upregulating TGF-β signaling as an immune checkpoint, helping to restrain excessive immune activation. This represents an adaptive state of “inflammaging” near the threshold of physiological balance. However, when TGF-β signaling can no longer be sustained, spinal cord health crosses an irreversible tipping point, leading to uncontrolled microglial immune activation in the dorsal column and, ultimately, severe pathological myelin damage.
This study reveals the critical role of TGF-β signaling as a microglial immune checkpoint during aging and significantly advances our understanding of microglia–myelin interactions. These findings provide new insights into age-related nervous system decline and may inform future personalized treatment strategies for demyelinating conditions, particularly those with lesions concentrated in the spinal cord.
The study was conducted in collaboration with researchers in China, the United States, and France. Funding was provided by the Swedish Research Council, Alltid Litt Sterkere, Neurofonden and Karolinska Institutet’s research initiative StratNeuro, among others. The researchers report no conflicts of interest.
“TGFβ signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration” Keying Zhu, Yun Liu, Jin-Hong Min, Vijay Joshua, Jianing Lin, Yue Li, Judith C. Kreutzmann, Yuxi Guo, Wenlong Xia, Elyas Mohammadi, Melanie Pieber, Valerie Suerth, Yiming Xia, Zaneta, Andrusivova, Jean-Philippe Hugnot, Shigeaki Kanatani, Per Uhlén, Joakim Lundeberg, Xiaofei Li, Stephen P.J. Fancy, Heela Sarlus, Robert A. Harris, Harald Lund, Nature Neuroscience, online 2 January 2026, doi: 10.1038/s41593-025-02161-4.