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<p>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 <i>Aurka</i> loss. <i>Bhlhe41-</i> or <i>Aurka</i>-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 <i>Aurka</i>-deficient microglia. CD22 blockade restored phagocytic function and remyelination in <i>Bhlhe41</i>-deficient mice. Notably, a conserved pattern of <i>CD22</i> upregulation was observed in human <i>PCDH9</i><sup>high</sup> microglia subsets with <i>BHLHE41</i> downregulation. These findings offer insights into potential therapeutic strategies to combat aging-related neurodegeneration and central nervous system functional decline.</p>

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Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • 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

摘要

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 PCDH9high microglia subsets with BHLHE41 downregulation. These findings offer insights into potential therapeutic strategies to combat aging-related neurodegeneration and central nervous system functional decline.