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<p>Alzheimer’s disease (AD), a leading cause of dementia, represents a critical unmet global medical need. While the precise mechanisms underlying AD pathogenesis remain elusive, increasing evidence underscores the pivotal role of neuroinflammation in driving cognitive impairment. N6-methyladenosine (m6A), an epigenetic modification regulating RNA metabolism, has been found to be dysregulated in AD. In this study, we used a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the effects of modulating astrocytic m6A levels on AD progression. Our comprehensive histological, biochemical, and transcriptomic analyses revealed that AD-cKO mice exhibited enhanced cognitive function, along with decreased astrogliosis and reduced neuroinflammation when compared to APP/PS1 control mice. Based on the conjoint analysis of MeRIP-seq and RNA-seq data, our mechanistic studies further demonstrated that the loss of Mettl14 in astrocytes significantly affected the expression of DUSP1, a negative regulator of inflammation, to mitigate MAPK signaling. These findings suggest that targeting m6A regulators, such as Mettl14, may represent a promising therapeutic strategy to control neuroinflammation in AD progression. This study also highlights the broader potential of epigenetic modulation as a novel approach for treating AD.</p><p></p>

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Astrocytic Mettl14 depletion enhances cognitive function by attenuating astrogliosis via the DUSP1/MAPK pathway in APP/PS1 mice: targeting neuroinflammation in Alzheimer’s disease

  • 期刊论文

  • 发表日期：

    2025年9月6日

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  • Yan Teng,
  • Jianli Xu,
  • Shu He,
  • Jin Yi,
  • Manjun Li,
  • Qin Tang,
  • Xingmin Chen,
  • Fan Wei,
  • Yanzhuo Liu,
  • Haisong Jiang,
  • Yang Xiang,
  • Jia-Ling Zhao,
  • Jing Yang,
  • Weidong Le,
  • Min Zheng,
  • Lu Yang

摘要

Alzheimer’s disease (AD), a leading cause of dementia, represents a critical unmet global medical need. While the precise mechanisms underlying AD pathogenesis remain elusive, increasing evidence underscores the pivotal role of neuroinflammation in driving cognitive impairment. N6-methyladenosine (m6A), an epigenetic modification regulating RNA metabolism, has been found to be dysregulated in AD. In this study, we used a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the effects of modulating astrocytic m6A levels on AD progression. Our comprehensive histological, biochemical, and transcriptomic analyses revealed that AD-cKO mice exhibited enhanced cognitive function, along with decreased astrogliosis and reduced neuroinflammation when compared to APP/PS1 control mice. Based on the conjoint analysis of MeRIP-seq and RNA-seq data, our mechanistic studies further demonstrated that the loss of Mettl14 in astrocytes significantly affected the expression of DUSP1, a negative regulator of inflammation, to mitigate MAPK signaling. These findings suggest that targeting m6A regulators, such as Mettl14, may represent a promising therapeutic strategy to control neuroinflammation in AD progression. This study also highlights the broader potential of epigenetic modulation as a novel approach for treating AD.