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

Yubo Zhou; Zonghui Huang; Bolong Lin; Ming Ma; Yize Hao; Juanjuan Liu; Wen Xu; Guangming Huang; Wei Mo; Xiaqiong Wang; Wei Jiang; Rongbin Zhou

doi:10.1038/s41423-024-01235-w

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

Cell Mol Immunol. 2025 Jan 1. doi: 10.1038/s41423-024-01235-w. Online ahead of print.

Authors

Yubo Zhou^#^{1

2}, Zonghui Huang^#^{2

3}, Bolong Lin^#², Ming Ma², Yize Hao², Juanjuan Liu⁴, Wen Xu⁵, Guangming Huang⁶, Wei Mo⁷, Xiaqiong Wang⁸, Wei Jiang⁹, Rongbin Zhou^{10

11

12

13}

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.
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.
³ Hefei National Research Center for Physical Sciences at the Microscale, Hefei, China.
⁴ Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
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.
⁶ School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui, 230001, China.
⁷ Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, China.
⁸ 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. [email protected].
⁹ 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. [email protected].
¹⁰ 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. [email protected].
¹¹ 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. [email protected].
¹² Hefei National Research Center for Physical Sciences at the Microscale, Hefei, China. [email protected].
¹³ Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. [email protected].

^# Contributed equally.

PMID: 39741193
DOI: 10.1038/s41423-024-01235-w

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.

Keywords: Alzheimer’s disease; GPCRs; Microglia; Neuroinflammation.