Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination.
basic_science · Level V
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- Record sourced from PubMed, PMID 41896238.
- Also identified by DOI 10.1038/s41467-026-71014-w.
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Abstract
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<sup>high</sup> microglia subsets with BHLHE41 downregulation. These findings offer insights into potential therapeutic strategies to combat aging-related neurodegeneration and central nervous system functional decline.