# TGFβ signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration

## TL;DR

Aging causes specific myelin damage in the spinal cord, which is protected against by TGFβ signaling in microglia.

## Contribution

The study reveals a region-specific TGFβ signaling mechanism in microglia that prevents myelin degeneration during aging.

## Key findings

- Myelin degeneration is prominent in the dorsal column during aging, with associated microglial changes.
- Disrupting TGFβ signaling in microglia leads to myelin loss and worsened neurological function with age.
- TGFβ signaling in microglia prevents myelin damage via an autocrine mechanism in the dorsal column.

## Abstract

Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia–myelin interactions are spatiotemporally regulated remains unexplored. Here, by examining spinal cord white matter tracts in mice, we determined that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of transforming growth factor beta (TGF)β signaling. Disrupting TGFβ signaling in microglia led to unrestrained microglial responses and myelin loss in the DC, accompanied by neurological deficits exacerbated with aging. Single-nucleus RNA-sequencing analyses revealed the emergence of a TGFβ signaling-sensitive microglial subset and a disease-associated oligodendrocyte subset, both of which were spatially restricted to the DC. We further discovered that microglia rely on a TGFβ autocrine mechanism to prevent damage of myelin in the DC. These findings demonstrate that TGFβ signaling is crucial for maintaining microglial resilience to myelin degeneration in the DC during aging. This highlights a previously unresolved checkpoint mechanism of TGFβ signaling with regional specificity and spatially restricted microglia–oligodendrocyte interactions.

Zhu et al. find that aging causes region-specific myelin damage in the spinal cord, which is counteracted by enhanced TGFβ signaling in microglia, revealing a protective mechanism for healthy aging.