本文選題：阿爾茨海默病 + SMC��； 參考：《深圳大學(xué)》2017年碩士論文

【摘要】：阿爾茨海默病(Alzheimer’s disease,AD)是一種與年齡相關(guān)的神經(jīng)退行性疾病,其主要特點(diǎn)是記憶缺失和認(rèn)知損傷。AD的病理特征主要表現(xiàn)為由Aβ沉積形成的老年斑塊和由tau蛋白過(guò)度磷酸化所形成的神經(jīng)纖維纏結(jié)(NFT)。此外,線粒體動(dòng)力學(xué)異常和功能障礙、自噬損傷和金屬離子內(nèi)穩(wěn)態(tài)紊亂等在AD的發(fā)展過(guò)程中也起著重要的作用。生物必需微量元素硒對(duì)維持中樞神經(jīng)系統(tǒng)的正常功能具有重要作用,長(zhǎng)期缺硒會(huì)引起包括AD在內(nèi)的多種腦疾病。硒甲基硒代半胱氨酸(SMC)是一種廣泛存在于植物中的天然有機(jī)硒化合物,與無(wú)機(jī)硒相比,具有毒性低,生物利用度高等特點(diǎn)。SMC具有明顯的抗氧化和抗腫瘤作用,但其在神經(jīng)退行性疾病包括AD中的作用尚無(wú)報(bào)道。本研究中,我們采用三轉(zhuǎn)基因AD模型小鼠(3×Tg AD),通過(guò)水迷宮、曠場(chǎng)實(shí)驗(yàn)、Western blot、ICP-MS、同步輻射X射線熒光(SR-XRF)、Gallys染色、尼氏染色和線粒體延時(shí)成像等方法,研究了SMC(3μg/m L)從2月齡開始給藥12個(gè)月對(duì)AD模型小鼠的相關(guān)病理指標(biāo)的干預(yù)作用和分子機(jī)制。研究發(fā)現(xiàn):1、SMC顯著提高AD模型小鼠的空間學(xué)習(xí)能力和記憶能力,并改善AD模型鼠的焦慮情緒;2、SMC抑制AD模型小鼠腦內(nèi)Aβ病理和tau病理,改善神經(jīng)元活性和突觸蛋白的表達(dá);3、SMC對(duì)AD模型小鼠腦內(nèi)多種金屬離子的含量和分布異常具有一定的調(diào)節(jié)作用;4、SMC通過(guò)調(diào)控雷帕霉素靶酶(mTOR)活性促進(jìn)自噬發(fā)生,進(jìn)而促進(jìn)自噬體生成自噬溶酶體,以清除錯(cuò)誤折疊蛋白。5、SMC通過(guò)激活A(yù)KT促進(jìn)線粒體的生物發(fā)生并抑制線粒體凋亡;通過(guò)調(diào)節(jié)線粒體能量代謝相關(guān)蛋白的表達(dá)糾正體內(nèi)ATP產(chǎn)生障礙;維護(hù)線粒體分裂融合的平衡并改善線粒體在神經(jīng)元軸突內(nèi)的運(yùn)輸障礙;保護(hù)線粒體膜電位和并抑制線粒體膜孔通道的過(guò)度開放�；赟MC對(duì)AD模型中Aβ病理和Tau病理的干預(yù)作用,對(duì)金屬離子內(nèi)穩(wěn)態(tài)的調(diào)控作用,對(duì)自噬受損的改善作用,及對(duì)線粒體動(dòng)力學(xué)和功能的保護(hù)作用,有望將SMC開發(fā)為一種潛在的AD干預(yù)藥物或保健品。
[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.
【學(xué)位授予單位】：深圳大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.16

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 馬云峰;王湘慶;郎森陽(yáng);;微管相關(guān)蛋白Tau蛋白及Tau病的研究進(jìn)展[J];解放軍醫(yī)學(xué)院學(xué)報(bào);2015年06期

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本文編號(hào)：1913957