SERPINA3N介导的神经炎性反应在TMT神经毒性中的作用与分子机理研究

Trimethyltin chloride (TMT) is a highly toxic organometal widely found in environments. It can accumulate in the human body through the respiratory tract, digestive tract and skin. In recent years, studies have found that TMT has a neurotoxic effect. Numerous epidemiological evidences suggest that TMT exposure may be one of the risk factors for degenerative neurological diseases such as Alzheimer's disease. However, its neurotoxic mechanism is complex and the molecular level is not fully investigated. Our previous experiments showed that the TMT exposed animal model showed severe learning and memory impairment, neuroinflammatory reaction and β-amyloid (Aβ) accumulation. SERPINA3N was found to be the most significantly changed protein in hippocampus of TMT treated mouse by quantitative proteomic analysis. A variety of bioinformatics analysis methods indicate that SERPINA3N is a key molecule involved in inflammatory response and activation of astrocytes and suggests that increased expression of SERPINA3N is closely related to the occurrence of Alzheimer's disease. IPA bioinformatics database molecular interaction network analysis indicates that SERPINA3N is directly related to ERK and NFκB proteins. Therefore, we hypothesized that TMT exposure activates the ERK-NFκB pathway by aberrantly overexpressing the SERPINA3N protein, resulting in the massive release of inflammatory factors such as TNF-α, IL-1β, IL-6 by astrocytes, leading to neurotoxicity. This project is expected to reveal the neurotoxic effects and molecular mechanisms of TMT, and provide experimental evidence for the prevention of TMT-induced neurological injury.

三甲基氯化锡（TMT）是广泛存在于生产与生活环境中的剧毒有机金属污染物。近年来研究发现TMT具有神经毒效应，但其神经毒性机制复杂，分子水平目前仍缺乏深入的研究。前期实验发现TMT暴露动物模型出现严重的学习记忆能力损伤、神经炎性反应和Aβ累积，同时通过定量蛋白组学分析海马脑区组织发现SERPINA3N的表达量变化最为显著。生物信息学分析指示SERPINA3N是参与炎性反应及激活神经星形胶质细胞的关键分子并且提示SERPINA3N表达量上升与阿尔兹海默症的发生密切相关。同时，IPA生物信息数据库分子互作网络分析指出SERPINA3N与ERK、NFκB蛋白有直接联系。因此，我们假设TMT暴露通过使SERPINA3N蛋白异常过量表达，激活ERK-NFκB通路，导致神经星形胶质细胞大量释放TNF-α，IL-1β，IL-6等炎性因子，造成神经元Aβ过度累积从而引起神经毒性。

三甲基氯化锡（TMT）是广泛存在于生产与生活环境中的剧毒重金属化合物，近年来发现TMT暴露是退行性神经疾病的高危因素，但神经毒效应机制尚未阐明。我们的研究结果发现TMT诱导的神经毒性，表现为癫痫样发作和学习记忆缺陷，海马神经元损伤、海马脑区神经递质紊乱、淀粉样前体蛋白（APP）过度表达等。我们在动物实验中，发现TMT诱导的神经毒性主要是通过促进A1型星形胶质细胞增生和促炎因子释放为主的神经炎性反应，并识别了SERPINA3N作为调控TMT神经毒性与神经炎性的新靶点。在体内和体外实验中我们也进一步验证了SERPINA3N对TMT神经毒性的作用。通过敲除SERPINA3N，揭示其介导A1型星形胶质细胞增生和促炎因子释放等过程在TMT致神经毒效应中的作用。同时研究发现，绿原酸（CGA）与矢车菊-3-O-葡萄糖苷（C3G）对TMT诱导神经毒性具有拮抗作用，并揭示CGA和C3G通过调控“肠-脑”轴拮抗TMT诱导神经毒性。本项目研究结果为揭示TMT神经毒效应的新机制和提出拮抗神经毒效应的新靶点提供理论与实验依据。