Zhu Ling, Zhou Tao, Wu Lei, Zhu Xuanang, Chen Lvan, Zhang Mi, Zhou Jing, Wang Fan
Department of Neurology, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of Technology, Jingmen, 448000, China.
Department of Emergency, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of Technology, Jingmen, 448000, China.
Sci Rep. 2025 Jul 10;15(1):24968. doi: 10.1038/s41598-025-09563-1.
Microglia and exosomes are intimately connected with the pathogenesis of Alzheimer's disease (AD). We aim to investigate the role and potential mechanisms of M2-like (anti-inflammatory) microglia-derived exosomes (M2-Exos) in AD. We utilized an Aβ-induced AD model in HT-22 neurons and mouse. The effects of M2-Exo on mitochondrial damage, ferroptosis, oxidative stress, and inflammation levels in the AD cell/animal models were evaluated using transmission electron microscopy, immunoblotting, and biochemical assay kits. Cognitive function in mouse was assessed through behavioral tests. In the AD cell/animal models, the effects of M2-Exo on the Wnt/β-catenin pathway were investigated through immunofluorescence and immunoblotting. AD cells were treated with HLY78 (Wnt/β-catenin pathway activator) to explore the modulation of the pathway. After knocking down TREM2 in M2-Exo, mitochondrial damage, ferroptosis, oxidative stress, and inflammation markers were reevaluated in AD cell and animal models. Aβ induced mitochondrial shrinkage and deformation in neurons, upregulated ACSL4, PTGS2, Fe2+/Fe, lipid peroxide (LPO), ROS, MDA, IL-6, IL-1β, and TNF-α, while it downregulated GPX4, FTH1, and GSH-PX. M2-Exo reversed the effects induced by Aβ both in vitro and in vivo, and M2-Exo improved cognitive function in AD mouse. HLY78 also reversed the effects induced by Aβ. M2-Exo increased the levels of β-catenin. BV2 cells converting to M2-like type increased TREM2 levels. Knocking down TREM2 in M2-Exos resulted in decreased neuronal β-catenin levels, reversing the beneficial effects of M2-Exo on AD cell and mouse models. M2-Exo TREM2 alleviates neuronal ferroptosis, inflammation, and oxidative stress in AD by activating the Wnt/β-catenin signaling pathway.
小胶质细胞和外泌体与阿尔茨海默病（AD）的发病机制密切相关。我们旨在研究M2样（抗炎）小胶质细胞衍生外泌体（M2-Exos）在AD中的作用及潜在机制。我们在HT-22神经元和小鼠中建立了Aβ诱导的AD模型。使用透射电子显微镜、免疫印迹和生化检测试剂盒评估M2-Exo对AD细胞/动物模型中线粒体损伤、铁死亡、氧化应激和炎症水平的影响。通过行为测试评估小鼠的认知功能。在AD细胞/动物模型中，通过免疫荧光和免疫印迹研究M2-Exo对Wnt/β-连环蛋白信号通路的影响。用HLY78（Wnt/β-连环蛋白信号通路激活剂）处理AD细胞以探索该信号通路的调节作用。在M2-Exo中敲低TREM2后，重新评估AD细胞和动物模型中的线粒体损伤、铁死亡、氧化应激和炎症标志物。Aβ诱导神经元线粒体收缩和变形，上调ACSL4、PTGS2、Fe2+/Fe、脂质过氧化物（LPO）、活性氧（ROS）、丙二醛（MDA）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）水平，同时下调谷胱甘肽过氧化物酶4（GPX4）、铁蛋白1（FTH1）和谷胱甘肽过氧化物酶（GSH-PX）水平。M2-Exo在体外和体内均逆转了Aβ诱导的效应，并且M2-Exo改善了AD小鼠的认知功能。HLY78也逆转了Aβ诱导的效应。M2-Exo增加了β-连环蛋白水平。BV2细胞向M2样类型转化会增加TREM2水平。在M2-Exos中敲低TREM2导致神经元β-连环蛋白水平降低，逆转了M2-Exo对AD细胞和小鼠模型的有益作用。M2-Exo TREM2通过激活Wnt/β-连环蛋白信号通路减轻AD中的神经元铁死亡、炎症和氧化应激。
