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

Abstract

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 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.