Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination
- Weixing Yan
- Yelin Zhao
- Hui Li
- Li Hong
- Qi Jia
- Di Zhu
- Dong Xiang
- Li Du
- Lang Hu
- Ruixue Bai
- Meizhen Xu
- Yangyang Tang
- Xinzhu Chen
- Yiwei Cao
- Wenyu Jia
- Siyu Wang
- Yuting Liu
- Jinfeng Ren
- Shuai Pan
- Yanbiao Shi
- Sijia Gao
- Fuxing Dong
- Jianhong Shi
- Jinghua Li
- Kuiyang Zheng
- Jing Yang
- Shuli Zhao
- Hui Wang
2026-03-27
Aging accelerates central nervous system remyelination failure and neurodegeneration. Microglia promote remyelination by phagocytosing myelin debris, but this function is impaired by aging-related CD22 upregulation. However, the molecular mechanisms counteracting premature aging-related microglial dysfunction and remyelination impairment remain unclear. Here, we report that Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination by restraining progressive CD22 upregulation. We identified that microglia-enriched Bhlhe41 was negatively autoregulated and inhibited by Aurka loss. Bhlhe41- or Aurka -deficient young mice exhibited aging-like microglial morphology, phagocytic deficits, progressive CD22 upregulation, and remyelination impairment in cuprizone-induced demyelination model. Conversely, ectopic Bhlhe41 expression induced hypertrophic microglia, and counteracted phagocytic deficits and CD22 upregulation in Aurka -deficient microglia. CD22 blockade restored phagocytic function and remyelination in Bhlhe41 -deficient mice. Notably, a conserved pattern of CD22 upregulation was observed in human PCDH9 high microglia subsets with BHLHE41 downregulation. These findings offer insights into potential therapeutic strategies to combat aging-related neurodegeneration and central nervous system functional decline.