Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling
Abstract 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 Aβ1−42-induced AD model in HT-22 neurons and m...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-09563-1 |
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| author | Ling Zhu Tao Zhou Lei Wu Xuanang Zhu Lvan Chen Mi Zhang Jing Zhou Fan Wang |
| author_facet | Ling Zhu Tao Zhou Lei Wu Xuanang Zhu Lvan Chen Mi Zhang Jing Zhou Fan Wang |
| author_sort | Ling Zhu |
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| description | Abstract 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 Aβ1−42-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. Aβ1−42 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 Aβ1−42 both in vitro and in vivo, and M2-Exo improved cognitive function in AD mouse. HLY78 also reversed the effects induced by Aβ1−42. 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. |
| format | Article |
| id | doaj-art-dfbcf04473a247fe9f9733b278257e0b |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-dfbcf04473a247fe9f9733b278257e0b2025-08-20T04:02:51ZengNature PortfolioScientific Reports2045-23222025-07-0115111510.1038/s41598-025-09563-1Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signalingLing Zhu0Tao Zhou1Lei Wu2Xuanang Zhu3Lvan Chen4Mi Zhang5Jing Zhou6Fan Wang7Department of Neurology, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyDepartment of Emergency, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyDepartment of Neurology, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyDepartment of Neurology, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyDepartment of Neurosurgery, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyDepartment of Neurology, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyCollege of Medical, Jingchu University of TechnologyDepartment of Neurosurgery, Jingmen Central Hospital, Jingmen Central Hospital, Jingchu University of TechnologyAbstract 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 Aβ1−42-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. Aβ1−42 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 Aβ1−42 both in vitro and in vivo, and M2-Exo improved cognitive function in AD mouse. HLY78 also reversed the effects induced by Aβ1−42. 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.https://doi.org/10.1038/s41598-025-09563-1Alzheimer’s diseaseM2-like microgliaExosomesTREM2Wnt/β-catenin pathwayFerroptosis |
| spellingShingle | Ling Zhu Tao Zhou Lei Wu Xuanang Zhu Lvan Chen Mi Zhang Jing Zhou Fan Wang Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling Scientific Reports Alzheimer’s disease M2-like microglia Exosomes TREM2 Wnt/β-catenin pathway Ferroptosis |
| title | Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling |
| title_full | Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling |
| title_fullStr | Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling |
| title_full_unstemmed | Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling |
| title_short | Microglial exosome TREM2 ameliorates ferroptosis and neuroinflammation in alzheimer’s disease by activating the Wnt/β-catenin signaling |
| title_sort | microglial exosome trem2 ameliorates ferroptosis and neuroinflammation in alzheimer s disease by activating the wnt β catenin signaling |
| topic | Alzheimer’s disease M2-like microglia Exosomes TREM2 Wnt/β-catenin pathway Ferroptosis |
| url | https://doi.org/10.1038/s41598-025-09563-1 |
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