三甲胺- n -氧化物损伤脑淋巴系统的星形胶质细胞和淋巴内皮细胞

IF 2.9 Q3 NEUROSCIENCES

IBRO Neuroscience Reports Pub Date : 2025-09-04 DOI:10.1016/j.ibneur.2025.09.001

Mei-lan Su , Hai-shui Duan , Qing-lin Wang , Ying Zhang , Xiao-man Shi , Juan Zeng , Wan-ning Tan , Yuan Chang , Song Wang

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引用次数: 0

摘要

背景：三甲胺- n -氧化物（TMAO）是一种依赖肠道微生物群的代谢物，参与了许多神经退行性疾病的发生和进展，如阿尔茨海默病和帕金森病，这些疾病与脑淋巴系统的破坏有关。然而，氧化三甲胺与脑淋巴系统的关系尚不清楚。本研究旨在探讨氧化三甲胺对脑淋巴系统星形细胞和脑膜淋巴管内皮细胞的影响。方法用不同浓度的氧化三甲胺处理星形胶质细胞和淋巴内皮细胞。分析细胞增殖或凋亡、炎症因子、核因子-κB （NF-κB）信号通路、活性氧（ROS）和功能蛋白如水通道蛋白-4 （AQP4）、胶质纤维酸性蛋白（GFAP）、S100β、claudin-5和Ocln的变化。C57BL/6雄性小鼠经TMAO处理后，颅内注射α -突触核蛋白（SNCA）。观察小鼠中脑腹侧神经元损伤、上述功能蛋白表达、脑脊液中SNCA和炎症因子水平。结果stmao激活NF-κB信号通路，增加星形胶质细胞和淋巴内皮细胞中核苷酸结合寡聚化结构域样受体家族pyrin结构域3 （NLRP3）、肿瘤坏死因子- α、白细胞介素(IL)-6、IL-1β和ROS水平，促进细胞凋亡；增加星形胶质细胞中GFAP和S100β的表达，降低AQP4的表达；降低淋巴内皮细胞中claudin-5和Ocln的表达。而NF-κ B信号通路抑制剂BAY11-7082可改善上述指标。动物实验表明，TMAO可诱导颅内炎症，影响脑淋巴系统功能蛋白的表达，增强小鼠脑内SNCA聚集。结论TMAO可激活NF-κB信号通路，损害小鼠脑淋巴系统和脑膜淋巴管的细胞功能，促进颅内炎症反应和SNCA沉积，这可能是TMAO参与神经退行性疾病的潜在机制。

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Trimethylamine-N-oxide damages astrocytes and lymphatic endothelial cells in the cerebral lymphatic system

Background

Trimethylamine-N-oxide (TMAO), as a gut microbiota dependent metabolite, is involved in the occurrence and progression of many neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, which are related to the disruption of the cerebral lymphatic system. However, the relationship between TMAO and cerebral lymphatic system remains to be elucidated. This study aimed to investigate the effects of TMAO on the astrocytes of the brain glymphatic system, and endothelial cells of the meningeal lymphatic vessels.

Methods

Astrocytes and lymphatic endothelial cells were treated with different concentrations of TMAO. Alterations in cell proliferation or apoptosis, inflammatory cytokines, the nuclear factor-kappaB (NF-κB) signaling pathway, reactive oxygen species (ROS), and functional proteins such as aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), S100β, claudin-5, and Ocln were analyzed. C57BL/6 male mice were treated with TMAO after which alpha-synuclein (SNCA) was injected intracranially. Neuronal damage and expressions of above functional proteins in the ventral midbrain, and levels of SNCA and inflammatory factors in the cerebrospinal fluid (CSF) of mice were assessed.

Results

TMAO activated the NF-κB signaling pathway, increased nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), tumor necrosis factor-alpha, interleukin (IL)-6, IL-1β, and ROS levels in astrocytes and lymphatic endothelial cells and promoted their apoptosis; increased the expression of GFAP and S100β, decreased the expression of AQP4 in astrocytes; decreased the expression of claudin-5 and Ocln in lymphatic endothelial cells. However, NF-κ B signaling pathway inhibitor BAY11–7082 improved the above indicators. Animal studies revealed that TMAO induced intracranial inflammation, affected the expression of functional proteins in the cerebral lymphatic system, and intensified SNCA aggregation in the mouse brain.

Conclusion

TMAO can activate the NF-κB signaling pathway and damage the cellular function of brain glymphatic system and meningeal lymphatic vessels, and promote intracranial inflammation and SNCA deposition in mice, which may be a potential mechanism for TMAO involvement in neurodegenerative diseases.

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