Zhou Yubo, Huang Zonghui, Lin Bolong, Ma Ming, Hao Yize, Liu Juanjuan, Xu Wen, Huang Guangming, Mo Wei, Wang Xiaqiong, Jiang Wei, Zhou Rongbin
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.
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.
Cell Mol Immunol. 2025 Feb;22(2):134-149. doi: 10.1038/s41423-024-01235-w. Epub 2025 Jan 1.
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.
小胶质细胞功能障碍相关的神经炎症是阿尔茨海默病（AD）的一个重要驱动因素，但其机制尚不清楚。在此，我们表明脱髓鞘通过AD中溶血磷脂酰丝氨酸（LysoPS）-GPR34轴促进神经炎症和认知障碍。在AD的5xFAD小鼠模型中，在疾病早期观察到脱髓鞘，并且髓鞘碎片中的LysoPS增加。通过基因或药理学方法降低髓鞘中LysoPS的含量或抑制其受体GPR34，可以减少小胶质细胞功能障碍和神经炎症，并改善小胶质细胞对Aβ的吞噬作用，随后减少5xFAD小鼠的Aβ沉积并恢复记忆。此外，在AD患者的大脑中也观察到LysoPS产生增加和小胶质细胞GPR34表达增加。这些结果揭示了脱髓鞘衍生的LysoPS在小胶质细胞功能障碍和AD病理中的致病作用，并表明阻断GPR34作为一种超越靶向Aβ的治疗策略。
