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Demyelination-derived lysophosphatidylserine promotes microglial dysfunction and neuropathology in a mouse model of Alzheimer’s disease

Cellular & Molecular Immunology volume 22, pages 134–149 (2025)Cite this article

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A Comment to this article was published on 14 January 2025

Abstract

Microglia dysfunction-associated neuroinflammation is an important driver of Alzheimer’s disease (AD), but the mechanism is poorly understood. Here, we show that demyelination promotes neuroinflammation and cognitive impairment via the lysophosphatidylserine (LysoPS)-GPR34 axis in AD. Demyelination is observed at the early stage and is accompanied by an increase in LysoPS in myelin debris in a 5xFAD mouse model of AD. Reducing the content of LysoPS in myelin or inhibiting its receptor GPR34 via genetic or pharmacological approaches can reduce microglial dysfunction and neuroinflammation and improve microglial Aβ phagocytosis, subsequently resulting in less Aβ deposition and memory restoration in 5xFAD mice. Furthermore, increased LysoPS production and microglial GPR34 expression were also observed in the brains of AD patients. These results reveal the pathogenic role of demyelination-derived LysoPS in microglial dysfunction and AD pathology and suggest that blocking GPR34 as a therapeutic strategy beyond targeting Aβ.

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Data availability

The sequencing data reported in this article have been deposited in the Gene Expression Omnibus (GEO accession number: GSE216209). Additional data supporting the presented findings are available in the manuscript and upon request from the corresponding author. All data are available in the main text or the supplementary materials. All the cell lines generated in this study are available from the authors.

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Acknowledgements

We thank Dr. Hui Fu for providing the Cnp-Cre mice. Human brain samples were provided by the National Health and Disease Human Brain Tissue Resource Center (Anhui Medical University). This research was supported by the National Key Research and Development Program of China (grant number 2020YFA0509101), the National Natural Science Foundation of China (grant numbers 81821001, 82130107, U20A20359), and the CAS Project for Young Scientists in Basic Research (YSBR-074).

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  1. These authors contributed equally: Yubo Zhou, Zonghui Huang, Bolong Lin.

Authors and Affiliations

  1. Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Yubo Zhou & Rongbin Zhou

  2. Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China

    Yubo Zhou, Zonghui Huang, Bolong Lin, Ming Ma, Yize Hao, Xiaqiong Wang, Wei Jiang & Rongbin Zhou

  3. Hefei National Research Center for Physical Sciences at the Microscale, Hefei, China

    Zonghui Huang & Rongbin Zhou

  4. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China

    Juanjuan Liu & Rongbin Zhou

  5. Neurology Department, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Wen Xu

  6. School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui, 230001, China

    Guangming Huang

  7. Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Wei Mo

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Contributions

YZ, XW, ZH, BL, YH, JL WX and MM performed the experiments; YZ, GH, WM, XW, WJ and RZ designed the research. YZ, XW, WJ and RZ wrote the manuscript. WJ and RZ supervised the project.

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Correspondence to Xiaqiong Wang, Wei Jiang or Rongbin Zhou.

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Competing interests

BL, WJ and RZ are co-inventors of a pending patent application (202110355421.6) submitted by University of Science and Technology of China. All the other authors declare that they have no competing interests. RZ is Deputy Editor-in-Chief of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Zhou, Y., Huang, Z., Lin, B. et al. Demyelination-derived lysophosphatidylserine promotes microglial dysfunction and neuropathology in a mouse model of Alzheimer’s disease. Cell Mol Immunol 22, 134–149 (2025). https://doi.org/10.1038/s41423-024-01235-w

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