失智症 (Dementia) 是因為疾病或腦部受創而導致腦部神經細胞死亡或不正常運作的一種症狀，而阿茲海默氏症 (Alzheimer’s disease, AD ) 是最為普遍的一種失智症，佔失智症患者的 60~80％ 。阿茲海默氏症是一種漸進式且不可逆的神經退化疾病，患者的大腦呈現萎縮的現象，就神經病理學來看，阿茲海默氏症主要有兩個病理特徵，細胞外的老化斑塊 (senile plaques) ，和 tau 微管蛋白過度磷酸化後瓦解，導致細胞內神經纖維糾結現象 (neurofibrillary tangles, NFTs) 。近年的研究認為，小分子具水溶性的一種胜肽鏈，β-類澱粉胜肽寡聚合物 (Aβ oligomers) 是引發神經細胞毒性，造成神經細胞死亡的主要因素。截至目前為止，尚未開發出有效治療阿茲海默氏症的藥物，所以預防阿茲海默氏症的發生顯得非常重要。本實驗目的是利用 Aβ1-42 類澱粉胜肽寡聚合物誘導大鼠初代皮質神經細胞毒性作為模式，並以銀杏萃出物 (EGb761) 作為正控制組，探討天然化合物保護神經細胞對抗 Aβ1-42 誘導神經細胞死毒性以達到預防阿茲海默氏症的發生，樣品包括川陳皮素 (nobiletin) ，橘皮素 (tangeretin) ，四甲氧基類黃酮 (TMF) ，芝麻素 (sesamin) ，芝麻酚 (sesamol) ，四氫薑黃素 (tetrahydrocurcumin) ，茶胺酸 (L-theanine) ，並且進一步的研究有效樣品對於神經細胞可能的保護機制。根據 MTT assay 細胞存活率的結果，七種樣品之中， tangeretin ， nobiletin 抗 Aβ1-42細胞毒性的效果較好，甚至比正控制組的效果更佳， TMF 也有不錯的效果。另外樣品清除自由基能力 (DCF-DA) assay 的結果顯示， EGb761 具有很強的清除 Aβ1-42 誘導胞內自由基的能力，但是其餘的樣品效果不佳；Western bolt 的結果顯示，EGb761 具有抑制聚集和解集 Aβ1-42 的效果，tangeretin 則可能具有促進 Aβ1-42的聚集的能力以降低其對神經細胞的毒性， nobiletin 對 Aβ1-42的聚集沒有影響，其可能透過其他機制保護神經細胞。

Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder. It is also the most common type of dementia, accounts for 60 to 80 percent of cases. Neuropathologically, there are three hallmarks of Alzheimer’s disease including brain atrophy, extracellular amyloid beta plaques and intracellular neurofibrillary tangles. Recent researches suggest that amyloid beta peptide induces neurontoxicity and causes neuronal cell death. Therefore, the objective of this study is to find the potential phytochemicals that can protect the brain neuron against Aβ1-42 oligomers induced neurotoxicity and thus prevent Alzheimer’s disease.
Samples under investigation include nobiletin, tengeretin, L-theanine, sesamol, sesamin, tetramethoxyflavone, tetrahydrocurcumin and Ginkgo biloba extract, (EGb761) which is the positive control. Cells were treated with various concentrations of samples for 30 min before exposed to 1 μM Aβ1-42, 24 hr at 37℃. In this research, the pure compounds were used to evaluate their potential neuroprotective effects against Aβ1-42 induced toxicity in primary rat cortical neurons by assessing the cell viability with MTT assay and further investigate their possible mechanisms.
According the results of viability assessed by MTT assay, the effective compounds are EGb761, nobiletin and tengeretin. In DCFDA assay, EGb761 has strong free radical scavenging activity but tangeretin and nobiletin do not have such activity. In Western blot, EGb761 was found to prevent Aβ1-42 oligomers formation and inhibits Aβ1-42 oligomers fibrillogenesis. Tangeretin possibly promotes the assembly Aβ1-42 into fibrils but nobiletin doesn’t have any effect on Aβ1-42. it indicates that tangeretin lowering Aβ1-42 oligomers toxicity may due to the promotion of Aβ1-42 fibrils production and nobiletin protects neurons from Aβ1-42 oligomers induced toxicity by other pathway.

中文摘要 I
Abstract II
縮寫表 IV
目錄 VI
圖次 IX
表次 XI
壹、前言 1
貳、文獻整理 2
一、阿茲海默氏症是最為普遍之失智症 2
二、阿茲海默氏症的兩大病理特徵 3
三、β-類澱粉胜肽 (β-Amyloid peptide, Aβ) 介紹 6
四、 Aβ 的聚合作用 9
五、 Aβ 對於神經細胞的毒性 13
六、阿茲海默氏症之藥物治療 17
七、大鼠初代腦皮質神經細胞 17
八、樣品介紹 22
(一)銀杏葉萃出物 (Ginkgo biloba extract, EGb761) 22
(二)芝麻酚 (Sesamol) 24
(三)芝麻素 (Sesamin) 24
(四)茶胺酸 (L-Theanine) 24
(五)四氫薑黃素 (Tetrahydrocurcumin) 25
(六)橘皮素 (Tangeretin) 25
(七)川陳皮素 (Nobiletin) 25
(八)四甲氧基類黃酮 (TMF) 26
参、研究目的與實驗架構 29
一、實驗目的 29
二、實驗架構 30
肆、材料與方法 32
一、實驗材料 32
(一) 實驗樣品 32
(二) 大鼠大腦初代皮質神經細胞 (Rat primart cortical neurons) 32
(三) 試劑與試藥 33
(四) 裝置與儀器設備 35
二、實驗方法 37
(一) 實驗用溶液配方 37
(二) 樣品配製 40
(三) Aβ 1-42定量與聚集 42
(四) 大鼠初代皮質神經細胞的分離與培養 42
(五) 以大鼠初代腦皮質神經細胞為模式之細胞試驗 48
(六) Tricine-SDS-PAGE 與西方墨點法 50
(七) Thioflavin T binding assay 52
伍、結果與討論 53
一、 Aβ1-42 寡聚合物對於初代神經細胞之毒性 53
二、 銀杏萃出物 (Ginkgo biloba extract, EGb761) 對初代神經細胞抵抗 Aβ1-42 寡聚合物毒性之保護功效 56
三、樣品對初代神經細胞抗 Aβ1-42 寡聚合物毒性之保護效果 62
(一) 芝麻酚 (Sesamol) 與芝麻素 (sesamin) 62
(二) 茶胺酸 ( L-Theanine ) 68
(三) 四氫薑黃素 (Tetrahydrocurcumin) 71
(四) 川陳皮素 (Nobiletin) 、橘皮素 (tangeretin) 和 tetramethoxyflavone (TMF) 74
四、樣品對初代神經細胞抗 Aβ1-42 寡聚合物毒性之機制探討 84
(一) 樣品對於細胞內自由基清除能力測定 84
(二) Aβ1-42 寡聚合物電泳分析以及樣品抑制其聚集之探討 88
陸、結論 93
柒、參考文獻 97

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