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Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination
Weixing Yan1,2, Yelin Zhao3, Hui Li1,2,4
1Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, School of Basic Medical Science, Xuzhou Medical University, Xuzhou, Jiangsu, China.
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 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.
Insights
The Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes central nervous system remyelination by restraining CD22 upregulation. This discovery offers potential therapeutic strategies for neurodegeneration.
Area of Science:
- Neuroscience
- Cellular Biology
- Aging Research
Background:
- Aging impairs microglia function, leading to neurodegeneration and failed central nervous system remyelination.
- CD22 upregulation in aging microglia inhibits their ability to clear myelin debris, a crucial step in repair.
Purpose of the Study:
- To elucidate molecular mechanisms counteracting premature aging-related microglial dysfunction.
- To identify pathways promoting remyelination despite aging.
Main Methods:
- Investigated the role of the Aurka-Bhlhe41 axis in microglial function using young mice models with Bhlhe41 or Aurka deficiency.
- Utilized the cuprizone-induced demyelination model to assess remyelination.
- Examined CD22 expression and microglial phagocytic capacity.
- Analyzed human microglia subsets for conserved molecular patterns.
Main Results:
- Aurka-Bhlhe41 axis deficiency in young mice mimicked aging-related microglial deficits, including impaired phagocytosis and increased CD22.
- Restoring Bhlhe41 expression counteracted these deficits and improved remyelination.
- CD22 blockade rescued microglial function and remyelination in deficient mice.
- Human microglia subsets showed similar CD22 upregulation and BHLHE41 downregulation patterns.
Conclusions:
- The Aurka-Bhlhe41 axis is critical for preventing age-related microglial dysfunction and promoting CNS remyelination.
- Targeting CD22 or modulating the Aurka-Bhlhe41 axis may offer therapeutic avenues for neurodegenerative diseases.
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