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Mettl3 regulates the pathogenesis of Alzheimer’s disease via fine-tuning Lingo2

Molecular Psychiatry volume 30, pages 4047–4063 (2025)Cite this article

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and diverse factors contribute to its pathogenesis. Previous studies have suggested the dysregulation of m6A modification involves in AD, but the underlying mechanism and targets remain largely unknown. In the present study, we have shown that the levels of Mettl3 and m6A modification are increased in specific brain regions of 5xFAD mice and post-mortem AD patients, respectively. Heterozygous deletion of neuronal Mettl3 (AD::Mettl3+/−) reduced Aβ plaques and inflammation, and improved learning and memory of AD mice, and vice versa for Mettl3 knock in (AD::Mettl3-KI). Mechanistically, we observed that the level of m6A modification of Lingo2 increased in 5xFAD mice and AD patients, which promoted the binding of Ythdf2 and enhanced the degradation of Lingo2 mRNA. The decreased level of Lingo2 promoted the interaction between APP and β-site amyloid precursor protein cleaving enzyme (Bace1), and subsequently enhanced Aβ production in AD mice, which can be inhibited by Mettl3 depletion. Both ectopic Lingo2 and the administration of Mettl3 inhibitor STM2457 significantly alleviated the neuropathology and behavioral deficits of AD mice. In summary, our study has revealed the important function of Mettl3 and m6A in the pathogenesis of AD and provided novel insight for the underlying mechanisms. Our study also suggests that m6A and Lingo2 could be potential therapeutic targets for AD.

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Fig. 1: The altered expression of Mettl3 and m6A in the brain of AD model mice and AD patients.
Fig. 2: Neuronal Mettl3 modulates Aβ production, inflammation and cognition of AD model mice.
Fig. 3: Mettl3 regulates the inflammation and cognitive function of AD model mice.
Fig. 4: Increased m6A modification of Lingo2 enhances its degradation via promoting YTHDF2 binding in the brains of AD model mice and human patients.
Fig. 5: Mettl3 regulates the interaction between Lingo2-Bace1 and APP-Bace1.
Fig. 6: Ectopic Lingo2 reduces the production of Aβ and inhibits the inflammation in the brain of AD model mice.
Fig. 7: The administration of Mettl3 inhibitor STM2457 enhances Lingo2 expression and ameliorates the deficits of AD model mice.

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Data availability

RNA-seq data have been deposited in GEO and the accession number is GSE268253.

Code availability

RNA-seq data have been deposited in GEO and the accession number is GSE268253.

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Acknowledgements

This work was supported in part by the Natural Science Foundation of Zhejiang Province (LD25H090001 to X.L.) and the National Key Research and Development Program of China (2017YFE0196600 to X.L.), and the Youth Innovation Promotion Association of CAS (Y2022040 to Y.Y.). We wish to thank the National Health and Disease Human Brain Tissue Resource Center for providing brain materials.

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  1. These authors contributed equally: Xingsen Zhao, Chengyi Ma, Qihang Sun.

Authors and Affiliations

  1. Department of Genetics and Metabolism, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China

    Xingsen Zhao, Qihang Sun, Xiaoli Huang, Wenzheng Qu, Binggui Sun & Xuekun Li

  2. The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China

    Xingsen Zhao, Qihang Sun & Xuekun Li

  3. Binjiang Institute of Zhejiang University, Hangzhou, 310053, China

    Xingsen Zhao, Ziqin Liu & Xuekun Li

  4. Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China

    Chengyi Ma, Yusheng Chen & Ying Yang

  5. NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China

    Aimin Bao & Binggui Sun

  6. Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China

    Ying Yang

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Contributions

XL conceptualized the project. XZ and QS performed immunostaining, qRT-PCR, western blots and immunoprecipitation with the help of XH and ZL CM, YC, YY and WQ analyzed MeRIP-seq data. XZ and A B analyzed human samples. XL, YY and BS discussed the data analysis. XL wrote the manuscript with the help of XZ, YY and BS.

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Correspondence to Binggui Sun, Ying Yang or Xuekun Li.

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Zhao, X., Ma, C., Sun, Q. et al. Mettl3 regulates the pathogenesis of Alzheimer’s disease via fine-tuning Lingo2. Mol Psychiatry 30, 4047–4063 (2025). https://doi.org/10.1038/s41380-025-02984-4

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