- 學位論文
探討小分子C-2對Protein-X促進amyloid beta寡聚合及細胞毒性之研究
Investigation of a small molecule, C-2, for its anti- Protein-X inducing amyloid beta oligomerization and cytotoxicity
摘要
阿茲海默氏症（Alzheimer’s disease, AD）已被視為常見的神經退化性疾病，主要病因為海馬迴的神經元受損，同時也引起認知功能障礙的出現。AD特徵包括由細胞內蛋白tau過度磷酸化所造成的神經纖維糾結（neurofibrillary tangles, NFTs）及細胞外類澱粉蛋白-β肽（β-amyloid peptide, Aβ）聚集形成的類澱粉斑塊（plaques）。目前，我們實驗室已發現，與年幼的小鼠相比，年老的AD模式鼠具有較高表現量的X蛋白。為了更進一步了解X蛋白在AD中的作用機制，我們藉由轉殖入X蛋白的SH-SY5Y細胞株作為本實驗使用的模式細胞。在細胞存活率方面以及西方墨點法的實驗中，從寡聚合物Aβ42中處理的細胞組別可以得知，經X蛋白的給予後會產生更多Aβ的聚集，使得細胞存活率降低，而處理小分子藥物的C-2能有效降低X蛋白所給予出的Aβ，進而達到拯救細胞的效果。因此，我們認為C-2可能透過抑制X蛋白而有效治療AD的小分子藥物。
並列摘要
Alzheimer’s disease (AD) has been considered as a common neurodegenerative disorder that causes hippocampal neurons damages and cognitive dysfunctions. AD features include neurofibrillary tangles (NFTs) caused by hyper-phosphorylation of intracellular tau protein, and extracellular β-amyloid (Aβ) plaques by Aβ aggregation. Our laboratory recently found that Protein-X level and the oligomerization of Aβ were concomitantly increased in aged triple transgenic AD mice (3xTg-AD) [PS1M146V, APPK670M/N671L, and tauP301L]. To further understand the mechanism of Protein-X in AD pathway, we established Protein-X stable-transfected SH-SY5Y cell line as the cell model in this experiment. In cell-based system and western blot analysis, Protein-X enhanced the formation of Aβ aggregation and the cytotoxicity is more than that in the present of Protein-X, implying that this cell-based system could serve as a platform for drug screening. Furthermore, we found that the small molecule, C-2, had the ability decrease the Aβ42 cytotoxicity induced by Protein-X. C-2 could be anticipated to develop a promising therapeutic agent for AD.
參考文獻
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