硒甲基硒代半胱氨酸通过调控自噬和线粒体功能干预阿尔茨海默症病理的机制研究

发布时间：2018-05-20 08:49

本文选题：阿尔茨海默病 + SMC　；参考：《深圳大学》2017年硕士论文

【摘要】：阿尔茨海默病(Alzheimer’s disease,AD)是一种与年龄相关的神经退行性疾病,其主要特点是记忆缺失和认知损伤。AD的病理特征主要表现为由Aβ沉积形成的老年斑块和由tau蛋白过度磷酸化所形成的神经纤维缠结(NFT)。此外,线粒体动力学异常和功能障碍、自噬损伤和金属离子内稳态紊乱等在AD的发展过程中也起着重要的作用。生物必需微量元素硒对维持中枢神经系统的正常功能具有重要作用,长期缺硒会引起包括AD在内的多种脑疾病。硒甲基硒代半胱氨酸(SMC)是一种广泛存在于植物中的天然有机硒化合物,与无机硒相比,具有毒性低,生物利用度高等特点。SMC具有明显的抗氧化和抗肿瘤作用,但其在神经退行性疾病包括AD中的作用尚无报道。本研究中,我们采用三转基因AD模型小鼠(3×Tg AD),通过水迷宫、旷场实验、Western blot、ICP-MS、同步辐射X射线荧光(SR-XRF)、Gallys染色、尼氏染色和线粒体延时成像等方法,研究了SMC(3μg/m L)从2月龄开始给药12个月对AD模型小鼠的相关病理指标的干预作用和分子机制。研究发现:1、SMC显著提高AD模型小鼠的空间学习能力和记忆能力,并改善AD模型鼠的焦虑情绪;2、SMC抑制AD模型小鼠脑内Aβ病理和tau病理,改善神经元活性和突触蛋白的表达;3、SMC对AD模型小鼠脑内多种金属离子的含量和分布异常具有一定的调节作用;4、SMC通过调控雷帕霉素靶酶(mTOR)活性促进自噬发生,进而促进自噬体生成自噬溶酶体,以清除错误折叠蛋白。5、SMC通过激活AKT促进线粒体的生物发生并抑制线粒体凋亡;通过调节线粒体能量代谢相关蛋白的表达纠正体内ATP产生障碍;维护线粒体分裂融合的平衡并改善线粒体在神经元轴突内的运输障碍;保护线粒体膜电位和并抑制线粒体膜孔通道的过度开放。基于SMC对AD模型中Aβ病理和Tau病理的干预作用,对金属离子内稳态的调控作用,对自噬受损的改善作用,及对线粒体动力学和功能的保护作用,有望将SMC开发为一种潜在的AD干预药物或保健品。
[Abstract]:Alzheimer's disease (AD) is an age-related neurodegenerative disease. The main features of AD are memory loss and cognitive impairment. The pathological features of AD are mainly age-related plaques formed by A 尾 deposition and neurofibrillary tangles formed by excessive phosphorylation of tau protein. In addition, mitochondrial kinetic abnormalities and dysfunction, autophagy and metal ion homeostasis also play an important role in the development of AD. Selenium, an essential microelement, plays an important role in maintaining the normal function of the central nervous system, and chronic selenium deficiency may cause many brain diseases, including AD. Selenomethylselenocysteine (SMC) is a natural organic selenium compound widely found in plants. Compared with inorganic selenium, SMC has the characteristics of low toxicity and high bioavailability. However, its role in neurodegenerative diseases, including AD, has not been reported. In this study, we used three transgenic AD mice with 3 脳 TG adriamycin, water labyrinth, open field experiments, Western blotl ICP-MS, synchrotron radiation X ray fluorescence (SR-XRF) Gallys staining, Nissl staining and mitochondrial delay imaging, etc. The effects and molecular mechanisms of SMC(3 渭 g / mL on the pathological parameters of AD model mice were studied in 12 months from the age of 2 months. It was found that SMC significantly increased the ability of spatial learning and memory in AD model mice, and improved anxiety in AD model mice. SMC inhibited A 尾 pathology and tau pathology in brain of AD model mice. Ameliorating neuronal activity and synaptophysin expression of SMC could promote autophagy by regulating the activity of rapamycin target enzyme mTORs and regulating the abnormal contents and distribution of multiple metal ions in brain of AD model mice. In order to remove the misfolded protein. 5SMC can promote mitochondrial biogenesis and inhibit mitochondrial apoptosis by activating AKT, and correct the ATP production barrier by regulating the expression of mitochondrial energy metabolism-related proteins in vivo, and promoting the formation of autophagy lysosome in autophagy. Maintain the balance of mitochondrial fission and fusion and improve mitochondrial transport barrier in neuronal axons, protect mitochondrial membrane potential and inhibit the excessive opening of mitochondrial membrane pore channel. Based on the intervention of SMC on A 尾 pathology and Tau pathology in AD model, the regulation of metal ion homeostasis, the improvement of autophagy damage, and the protection of mitochondria dynamics and function were observed. SMC is expected to be developed as a potential AD intervention drug or health care product.
【学位授予单位】：深圳大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.16

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