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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

Molecular Psychiatry (2025)Cite this article

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Abstract

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.

This graphic abstract illustrates the impact of Mettl14-mediated m6A modification on Alzheimer’s disease (AD) pathogenesis. Alzheimer’s disease, a leading cause of dementia, involves significant neuroinflammation. The study utilizes a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the role of m6A modification in astrocytes, the findings suggest that targeting m6A regulators like Mettl14 offers potential therapeutic benefits for controlling neuroinflammation in AD.

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Fig. 1: Increased m6A and m6A ‘Writers’ in astrocytes in response to Aβ pathology both in vivo and in vitro.
Fig. 2: Characterization of mice with region-specific depletion of Mettl14 in astrocytes.
Fig. 3: Region-specific depletion of astrocytic Mettl14 impacts Aβ pathology and morphology of hippocampal neurons in APP/PS1 mice.
Fig. 4: Depletion of Mettl14 in astrocytes mitigates astrocyte activation and neuroinflammation in APP/PS1 mice.
Fig. 5: Bioinformatic analysis of MeRIP-seq and RNA-seq data with in vitro validation of key candidate genes.
Fig. 6: Dusp1 as the critical target of Mettl14-mediated m6A modification to regulate astrocyte activation via MAPK pathways.

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Data availability

The data that support the findings of this study are available from the corresponding author YL, upon request. The raw MeRIP-Seq data is available on Dryad at https://doi.org/10.5061/dryad.pc866t217.

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Acknowledgements

The authors would like to thank Dr. Li Hua-bing (Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, School of Medicine, Shanghai Jiao Tong University) for his support in providing the Mettl14-loxp mice.

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Author notes

  1. These authors contributed equally: Yan Teng, Jianli Xu, Shu He.

Authors and Affiliations

  1. Institute of Neurology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China

    Yan Teng, Jianli Xu, Yang Xiang, Jia-Ling Zhao, Jing Yang, Weidong Le & Lu Yang

  2. School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China

    Yan Teng, Jianli Xu, Shu He, Jin Yi, Manjun Li, Qin Tang, Xingmin Chen, Fan Wei, Yanzhuo Liu, Haisong Jiang, Min Zheng & Lu Yang

  3. Neurology Program, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Weidong Le

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Contributions

YL conceptualized the project. YL and TY contributed to experimental design and data interpretation. TY, XJL, and HS performed experiments and analyzed data with the assistance of YJ, LMJ, TQ, CXM, WF and LYZ. YL wrote the manuscript with input from all the authors. XY, ZJL and YJ helped with the discussion, YL, ZM and LWD supervised the project, provided resources, and acquired funds.

Corresponding authors

Correspondence to Weidong Le, Min Zheng or Lu Yang.

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The authors declare no competing interests.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. Ethical approval was obtained from the the Ethics Committee of University of Electronic Science and Technology of China. Informed consent was obtained from all participants involved in this study.

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Teng, Y., Xu, J., He, S. et al. Astrocytic Mettl14 depletion enhances cognitive function by attenuating astrogliosis via the DUSP1/MAPK pathway in APP/PS1 mice: targeting neuroinflammation in Alzheimer’s disease. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03211-w

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