- 學位論文
美伐他汀減少乙型類澱粉蛋白神經毒性機轉之研究
The Study on Mechanism of Mevastatin Protects from Amyloid β-induced Neurotoxicity
摘要
阿茲海默症(Alzheimer’s Disease，簡稱AD)是一種持續性神經性退化疾病，也是失智症中最普遍的成因。阿茲海默症的症狀因人而異，通常第一個被注意到的症狀便是短期記憶障礙，病人可能會重複發問。難以記得目前的對話、事件等。慢慢的，記憶力的衰退嚴重時甚至影響到病人社交生活或工作。藉著病理解剖觀察到阿茲海默病人的大腦皮質出現斑塊(Plaques)和神經纖維糾結(Neurofibrillary Tangles簡稱NFTs)，其中斑塊主要由名為乙型類澱粉蛋白(β amyloid，簡稱Aβ)的蛋白質所組成，神經纖維糾結(NFTs)的形成與一種名為(Tau)蛋白質的過磷酸化狀態有關。這些斑塊與糾結使得神經細胞嚴重變形，互相纏繞並且堆疊成團造成神經細胞的死亡，最終導致AD症狀的產生。 史他汀類(Statin)藥物的是典型的降血脂藥物，被用於控制血液中膽固醇的含量以及預防心血管疾病，特別是常使用於治療第二型糖尿病。由於流行病學上的研究指出，第二型糖尿病與阿茲海默症具有相當的關聯性，因此史他汀類藥物被認為可能也具有對抗阿茲海默症的效果，但其詳細的分子機轉目前並不十分明瞭。因此在本研究中，我們利用美伐他汀(mevastatin)作為研究對象，希望透過In vitro的方式，來探討史他汀類藥物可能的抗阿茲海默症分子機轉。初步的結果發現，實驗室的培養的神經細胞在加入美伐他汀時，具有明顯活化AMPK的能力，而這些被誘發的AMPK活性對於mevastatin對抗乙型類澱粉蛋白的神經保護效果是必需的。此外，在給予mevastatin時，乙型類澱粉蛋白所導致之Tau蛋白過磷酸化現象也顯著的抑制。總和以上的發現我們推測，美伐他汀可能會透過提升AMPK的活性來達到對抗乙型類澱粉蛋白的毒性，並進一步抑制Tau過磷酸化，來達到其神經保護的效果。
關鍵字
阿茲海默症並列摘要
Alzheimer's disease (Alzheimer's Disease, referred to as AD) is a continuous neurodegenerative disease, is the most common cause of dementia. Symptoms of Alzheimer’s disease vary, usually the first symptom noticed is that short-term memory impairment, and the patient may be repeated questions. Difficult to remember that the current dialogue, events, and so on. Slowly, the decline of memory and even affect the patient in serious social life or work. Observed by pathological anatomy of the cerebral cortex of Alzheimer patients appear plaque (Plaques) and neurofibrillary tangles (Neurofibrillary Tangles called NFTs), in which plaques mainly composed of beta-amyloid protein called (β amyloid, called Aβ) composed of protein, neurofibrillary tangles formation and called Tau proteins through phosphorylation states. These plaques and tangles so severely deformed nerve cells, each stack into the group winding and causing the death of nerve cells, eventually leading to the generation of AD symptoms. History Statins (Statin) drugs is a typical cholesterol-lowering drugs, is used to control blood cholesterol and prevention of cardiovascular diseases, in particular often used in the treatment of type II diabetes. Because epidemiological studies have indicated that type II diabetes and Alzheimer's disease has considerable relevance, so history is that statins may also have effects against Alzheimer's disease, but the detailed molecular mechanism switch current is not very clear. Therefore, in this study, we used mevastatin as the object of study. In vitro approach aims to explore the history of statins may be anti-molecular mechanisms of Alzheimer's disease. Preliminary results showed that laboratory cultured neural cells by adding mevastatin, the ability to have a significant activation of AMPK, which was induced AMPK activity against beta-amyloid for the mevastatin neuroprotective effect of protein is required The. In addition, given mevastatin, the beta-amyloid caused by the Tau protein phosphorylation has also significantly inhibited. The sum of these findings we hypothesized that mevastatin may be through enhancing the activity of AMPK to achieve against the toxicity of beta-amyloid protein, and further inhibit the phosphorylation of Tau had to reach its neuroprotective effect.
並列關鍵字
Alzheimer參考文獻
延伸閱讀
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