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研究生:黃冠華
研究生(外文):Kuan-Hua Huang
論文名稱:利用日本腦炎病毒建立阿茲海默症模式之研究
論文名稱(外文):Study of Alzheimer's disease model induced by Japanese encephalitis virus
指導教授:吳彰哲
指導教授(外文):Chang-Jer Wu
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:93
中文關鍵詞:日本腦炎病毒阿茲海默症
外文關鍵詞:japanese encephalitis virusAlzheimer's disease
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日本腦炎病毒 (Japanese encephalitis virus, JEV),為感染腦部而引發腦炎的病毒,屬於黃質病毒科,所造成之死亡率高達 5~60%。此外,病情康復者也會留下嚴重神經系統後遺症並出現智能及學習障礙等現象。阿茲海默症為一種神經退化性疾病,常發生在老年族群,會造成智能退化、行動不便,缺乏空間感和方向感及情緒不穩等症狀。基於日本腦炎會造成智能退化及嚴重神經系統受損,此與阿茲海默症相似,故探討日本腦炎與阿茲海默症的相關性,並以抗氧化物質表沒食子兒茶素沒食子酸酯 (Epigallocatechin-3-gallate, EGCG) 及維生素 C (Vitamin C, Vit. C) 添加觀測其是否具有改善效果。經動物實驗顯示,小鼠感染日本腦炎病毒時,其APP (amyloid precursor protein)、BACE (β-secretase) 等與阿茲海默症相關因子表現量增高,並具有劑量依賴性;運甲狀腺素蛋白 (transthyretin, TTR) 的表現則有下降;誘導型一氧化氮合酶 (inducible nitric oxide synthase, iNOS) 表現也有增高並在海馬迴及皮質出現發炎及結構鬆散現象,且有少許乙型類澱粉質 (beta-amyloid, Aβ) 產生。在低劑量感染下,隨時間增加,感染小鼠其記憶及學習力皆有下降之趨勢並與老年小鼠其值相近,且海馬迴及皮質皆出現有 Aβ 沉積產生。此外,TTR 的表現也隨之下降,APP 及 BACE 也略為提升。細胞實驗發現,神經細胞感染日本腦炎病毒後,APP、BACE 及 iNOS 表現量增加,但 TTR 表現量下降。添加抗氧化物質 EGCG 及 Vit. C 則可改善此現象,並以預防效果較佳。由此推測,日本腦炎病毒感染可能在腦部造成與阿茲海默症類似的基因表現及智能退化;抗氧化物質 EGCG 及 Vit. C 則具有預防及改善日本腦炎病毒造成之 APP、TTR、BACE、iNOS 等基因改變之效果。
Japanese encephalitis virus (JEV), a neurotropic flavivirus, is one of the major causes of acute encephalitis in human. The mortality range between 5 to 60%. However, it often results in severe neurological sequelae and learning disabilities after rehabilitation. Alzheimer’s disease (AD), a progressive neurodengenerative disorder, is the most common form of dementia among the elderly. It causes mental deterioration, mobility, lack of sense of space and sense of direction and mood swings symptoms. Japanese encephalitis can cause degradation of intelligence and serious damage of the nervous system which is similar to Alzheimer’s disease. The aims of this study are to explore the pathologic correlation of the Japanese encephalitis virus and the Alzheimer’s disease, and to use the antioxidants EGCG (Epigallocatechin-3-gallate) and Vit. C (Vitamin C) to observe whether they can attenuate the inflammation caused by Japanese encephalitis virus. Animal experiments showed that mice infected with JEV, the expressions of APP (amyloid of precursor protein) and BACE (β-secretase), Alzheimer’s disease related factors, increased in a dose-dependent manner. In addition, the expression of TTR (transthyretin) decreased, so did iNOS and beta-amyloid (Aβ), some loosely structures were observed in the hippocampus and cortex.
The memory and the learning ability of the mice infected with low-dose JEV decreased with time elapse, similar to 16 month old mice. And Aβ were observed in the hippocampus and cortex. However, antioxidant compounds EGCG and Vit. C increased the expressions of APP, BACE and iNOS; while the expression of TTR decreased in neuron cell. In summary, our results showed that JEV infection may result in the Alzheimer’s disease related genes expression and inteligence degradation similar to Alzheimer’s disease. The antioxidants EGCG and Vit. C can improve the expressions of APP, TTR, BACE and iNOS.

目錄
目錄 i
圖目錄 iii
中文摘要 1
Abstract 3
壹、緒論 5
一、日本腦炎 ( Janpanese encephalitis, JE ) 5
1. 日本腦炎流行病學 5
2. 日本腦炎病毒簡介 6
3. 日本腦炎傳染途徑 7
4. 日本腦炎的臨床症狀及後遺症 8
5. 日本腦炎造成之免疫反應 8
6. 中樞神經系統與氧化壓力 11
二、阿茲海默症(Alzheimer’s disease) 12
1. 阿茲海默症流行病學 12
2. 阿茲海默症簡介 12
2.1分類: 13
2.2 症狀: 13
2.3 危險因子: 14
3. 阿茲海默症之治病機制及相關因子 15
3.1乙型類澱粉質前趨蛋白質 (amyloid precursor protein , APP) 16
3.2 Beta-site APP cleaving enzyme (β-secretase, BACE) 16
3.3乙型類澱粉質 (Aβ) 17
3.4 Transthyretin (TTR) 17
4. 阿茲海默症之治療與預防 18
三、 實驗目的 19
貳、實驗材料與方法 20
一、 實驗材料 20
1. 細胞株 20
2. 實驗動物 20
3. 細胞培養之培養基 20
4. MTS assay 試劑 21
5. 病毒斑試驗試劑 (Plaque assay) 21
6. RNA 萃取套組 22
7. 反轉錄反應試劑 22
8. 即時定量聚合酶鏈鎖反應試劑 22
9. 蛋白質萃取試劑 (Lysis buffer) 及濃度測定試劑 23
10. 蛋白質定量 23
11. SDS-PAGE 23
12. 蛋白質點墨法之材料、試劑、緩衝液 24
13.抗氧化物質 25
14.組織切片 25
二、 儀器設備及分析軟體 25
三、 實驗方法 26
細胞實驗 26
1. 細胞培養 26
2. 混合膠質細胞 (mixed glia cell) 初代培養 (primary culture) 26
3. 日本腦炎病毒生產方式 27
4. 日本腦炎病毒效價測定 28
5. 細胞存活率試驗 (MTS assay) 28
6. 測定 EGCG 或 Vit. C 對於 JEV 在細胞的預防及治療效果 29
7. 細胞 RNA 萃取與分析 29
8. 反轉錄反應 (reverse transcription, RT) 30
9. 即時聚合酶連鎖反應 (Real-time polymerase chain reaction) 31
動物實驗 32
1. 建立日本腦炎病毒感染小鼠之模式 32
2. 腦部組織收集及萃取 32
3. BCA定量分析 32
4. SDS-PAGE與轉漬 33
5. 西方墨點法 (Western blot) 分析 33
6. 腦部組織灌流、切片與染色 34
7. 組織RNA萃取與分析 35
8. 水迷宮試驗 (台灣大學生化科技系潘子明老師實驗室提供) 36
9. 統計分析 38
參、結果 40
肆、討論 47
伍、結論 54
陸、參考文獻 55
柒、圖 64

圖目錄
Fig. 1 Survival rate of infected mice by different JEV dosage. 64
Fig. 2 The expression of Alzheimer’s disease related mRNA with different dose of JEV infected mice. 65
Fig. 3 The expression of APP with different dose of JEV infected mice. 66
Fig. 4 Effects of JEV infection with different dose on β-secretase activity in mice brain. 67
Fig. 5 Inflammation and impairment in the brain hippocampus of mice infected by different JEV dosage. 68
Fig. 6 Inflammation and impairment in the brain cortex of mice infected by different JEV dosage. 69
Fig. 7 Aβ immunofluorescence in the hippocampus of mice infected by different JEV dosage. 70
Fig. 8 TTR immunofluorescence in the hippocampus of mice infected by different JEV dosage. 71
Fig. 9 Aβ immunofluorescence in the cortex of mice infected by different JEV dosage. 72
Fig. 10 TTR immunofluorescence in the cortex of mice infected by different JEV dosage. 73
Fig. 11 The distance swum to find the platform in 1-9 months mice by JEV infected. 74
Fig. 12 The latency time to find the platform in 1-9 months mice by JEV infected. 75
Fig. 13 The spatial memory of JEV-infected mice for 1-9 month. 76
Fig. 14 The working memory of JEV-infected mice for 1-9 month. 77
Fig. 15 Aβ accumulation in the hippocampus of JEV-infected mice for 1-9 month. 78
Fig. 16 Aβ accumulation in the cortex of JEV infected mice for 1-9 month. 79
Fig. 17 Aβ immunofluorescence in the hippocampus of JEV-infected mice for 1-9 month. 80
Fig. 18 TTR immunofluorescence in the hippocampus of JEV-infected mice for 1-9 month. 81
Fig. 19 Aβ immunofluorescence in the cortex of JEV-infected mice for 1-9 month. 82
Fig. 20 TTR immunofluorescence in the cortex of JEV-infected mice for 1-9 month. 83
Fig. 21 The expression of Alzheimer’s disease related mRNA with 1-9 month of JEV infected mice. 84
Fig. 22 The expression of APP with 1-9 month of JEV infected mice. 85
Fig. 23 Effects of JEV infection with 1-9 month on β-secretase activity in mice brain. 86
Fig. 24 The cell viability of neuroblastoma cell when adding different dose of EGCG. 87
Fig. 25 The cell viability of neuroblastoma cell when adding different dose of Vit. C. 88
Fig. 26 Viability of neuroblastoma cell that treated with EGCG and Vit. C after infection by JEV. 89
Fig. 27 Viability of neuroblastoma cell that treated with EGCG and Vit. C before infection by JEV. 90
Fig. 28 Comparison of cell viability between pre-infection and post-infection of EGCG and Vit. C on JEV-infected Glial cell. 91
Fig. 29 The mRNA expression of Alzheimer’s disease-related protein of EGCG and Vit. C pre-infection on the JEV-infected Glial cell. 92
Fig. 30 The mRNA expression of Alzheimer’s disease-related protein of EGCG and Vit. C post-infection on the JEV-infected Glial cell. 93


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