指導教授：潘子明臺灣大學：生化科技學系張光曜Chang, Kuang-YaoKuang-YaoChang2014-11-262018-07-062014-11-262018-07-062014http://ntur.lib.ntu.edu.tw//handle/246246/261624腦中類澱粉樣蛋白 (amyloid β, Aβ) 和磷酸化 tau 蛋白 (phosphorylated tau protein, p-tau) 堆積及其所引發氧化壓力、發炎反應為造成阿茲海默症 (Alzheimer’s disease, AD) 之元兇。本研究使用雄性八周齡之 Sprague-Daw1ey 大鼠，以氯化鋁誘導產生阿茲海默症造成記憶學習能力之衰退。動物實驗結果證實山藥為基質的紅麴 (Monascus purpurues) 發酵產物—紅麴山藥 (red mold dioscorea, RMD) 能有效改善鋁誘發的認知功能損傷。在大鼠腦中，鋁使 Aβ、p-tau 和類澱粉樣前驅蛋白 (amyloid precursor protein, APP) 表現量增加、乙醯膽鹼酯酶 (acetylcholin esterase, AChE) 活性增加，同時引發腦脊髓液 (cerebraspinal fluid, CSF) 中阿茲海默症生物標記的變化，RMD 能回復此些變化，亦能降低由鋁、Aβ 和 p-tau 所引起之腦中氧化壓力和發炎反應。本研究中阿茲海默症用藥愛憶欣 (Aricept) 的功效亦一併評估，但效果並不顯著。肝腎功能指標和組織切片未觀察出 RMD 對大鼠之不良影響。本研究顯示紅麴山藥可以透過減少腦中自由基生成和增加抗氧化酵素能力，減緩腦中氧化壓力、Aβ 和 p-tau 生成，亦能減輕發炎反應，使得鋁誘發之記憶學習能力損傷得以改善，且效果較藥物愛憶欣佳。本研究結果顯示，紅麴山藥具延緩與改善阿茲海默症之潛力，而其複合性功效與安全性更使紅麴山藥在預防醫學領域占一席之地。Oxidative stress and neuroinflammation induced from accumulation of amyloid β (Aβ) and phosphorylated tau protein (p-tau) are the main causes of Alzheimer’s disease (AD). In this study, aluminum chloride is administered daily to male Sprague-Daw1ey rats via oral gavage to induce AD pathology and degeneration of memory and learning ability. We examined the beneficial effects of Monascus purpureus fermented product (red mold dioscorea, RMD) in this model. First, RMD mitigated cognitive impairment in behavior tests of this study. We then found that RMD restored AD pathology in brain induced by aluminum, including accumulation of Aβ and p-tau, increased amyloid precursor protein (APP) levels, elevated acetylcholinesterase (AChE) activity, and biomarker changed in cerebrospinal fluid (CSF). Furthermore, RMD could reduce oxidative stress and inflammation in rat’s brain. Effects of Aricept, an approved drug for AD, was also examined in this study and showed no significant improvement. Through examining serum biochemical index and tissue of liver and kidney, RMD had no adverse effect on rats in whichever doses. This study shows that by suppressing free radical generation and activating antioxidant enzyme, RMD can reduce oxidative stress and inflammation and then ameliorates AD pathology. Thus, protects rats against aluminum-induced memory and learning ability deficit. In addition, these advantageous effects of RMD on AD are even better than Aricept’s. The protective effect of AD and multifunctional property of RMD makes it a potential candidate in AD treatment and preventive healthcare.縮寫表…………………………………………………………………………………… i 中文摘要………………………………………………………………………………… iii 英文摘要………………………………………………………………………………… iv 目錄……………………………………………………………………………………… V 表目錄…………………………………………………………………………………… vii 圖目錄…………………………………………………………………………………… viii 第一章、文獻回顧…………………………………………………………………….…. 1 ㄧ、阿茲海默症………………………….…………………………………………… 1 (一) 阿茲海默症病徵與階段………………………..……………………………. 1 (二) 阿茲海默症病因………………………..……………………………………. 2 (三) 阿茲海默症遺傳因子………………………..………………………………. 13 (四) 阿茲海默症生物標記……………………………………………..….……… 15 二、阿茲海默症與鋁…………………………………………………………………. 17 (一) 鋁………………………………..……………………………………………. 17 (二) 鋁的神經毒性………………………………………………………………... 17 (三) 鋁與阿茲海默症…………………………………………………………..…. 20 三、紅麴菌………………………………………………………………………..…. 24 (ㄧ) 紅麴菌之特性…………………………………………………………..……. 25 (二) 紅麴之代謝產物…………………………………….………………..……… 25 (三) 紅麴與阿茲海默症…………………………………………………..………. 27 第二章、研究動機與大綱……………………………………………………..……….. 28 第三章、材料與方法……………………………………………………………………. 30 ㄧ、實驗材料………………………………………………………………………… 30 (一) 儀器………………………..………………………………………………….. 30 (二) 藥品…………...……………………………………………………………… 30 二、實驗方法………….………………………………………………………………. 31 (一) 動物實驗…………………………..…………………………………………. 31 (二) 生理與生化分析………………..…………………………………………..... 38 (三) 統計分析……………………..….…………………………………………… 43 第四章、結果與討論…………………………..………………………….…………….. 44 ㄧ、紅麴山藥對鋁誘導大鼠之學習記憶能力改善情形………………….………… 44 二、紅麴山藥對於鋁誘導產生阿茲海默症病徵的改善效果...…………..…..……. 53 三、紅麴山藥改善鋁誘導大鼠腦中之氧化壓力與發炎反應……..…..……………. 61 四、綜合討論…………………………………………………………………….……. 73 第五章、總結……………………………………………………………………….…… 78 第六章、參考文獻………………………………………………………………………. 795490892 bytesapplication/pdf論文公開時間：2019/08/04論文使用權限：同意有償授權(權利金給回饋學校)阿茲海默症鋁大鼠紅麴山藥類澱粉樣蛋白thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/261624/1/ntu-103-R01b22054-1.pdf