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錄 10927
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G0496866076
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助
教 建檔完成
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核
索
書 查核完成
號
學
校 輔仁大學
名
稱
系
所 營養科學系
名
稱
舊
系
所
名
稱
學
496866076
號
研
究 唐銘圻
生
(中)
研
究 Ming-Chi Tang
生
(英)
論
文 葉酸補充與 Memantine 對 Tg2576 小鼠腦部基因之調節與降低類澱粉蛋白誘
名
發神經細胞毒性之機制
稱
(中)
論
文 Folate supplementation and Memantine treatment modified gene expression profile
名 in brain of Tg2576 transgenic mice and protected against Abeta-induced neuron
稱 toxicity
(英)
其
他
題
名
指
導
許瑞芬
教
授
(中)
指
導
Rwei-Fen S.Huang
教
授
(英)
校
內
全
文 2015.11.1
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封面 中英文摘要 縮寫表 致謝 目錄 第一章 前言 第二章 文獻回顧與研究目
的 第三章 實驗架構與材料方法 第四章 結果-I 第四章 圖表-I 第五章 討論-I
第四章 結果-II 第四章 圖表-II 第五章 討論-II 第六章 結論 第七章 參考文獻
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memantine 葉酸補充 類澱粉蛋白 細胞程式凋亡 粒線體膜電位去極化 鈣離
鍵
子
字
(中)
關
鍵 memantine folate supplementation amyloid-β apoptosis mitochondria membrane
字 potential depolarization calcium
(英)
Memantine 為治療阿茲海默症 (Alzheimer’s disease; AD) 病患之臨床藥物，
但治療效果有限制性。臨床研究指出葉酸補充降低 AD 風險，但機轉尚未
明確。故本研究擬探討葉酸補充合併 Memantine 保護類澱粉蛋白 (Amyloid
β; Aβ) 誘發腦神經傷害之影響及作用機轉。以基因轉殖小鼠 Tg2576 為研
究模式，誘發 AD 相關之腦部損傷，並分成餵食 Memantine (30 mg/kg/day)
與補充葉酸 (8 mg/kg/day) 合併 Memantine 兩組。小鼠大腦利用微陣列
(cDNA microarray) 觀察全基因表現再以 GeneSpring GX10 軟體分析，發現相
較於單純以 Memantine 治療之小鼠，葉酸補充合併 Memantine 治療之小鼠
腦部有 74 個基因顯著正向調控兩倍以上，其中含神經發育相關轉錄因
子、促神經新生、突觸新生與形成、神經傳遞物質受器等腦部功能相關基
因，這些基因表達改變可能與小鼠空間記憶能力改善有相關。以人類神經
摘 母細胞瘤細胞株 SH-SY5Y 為研究模式，以葉酸 500 μM 和 1000 μM、
Memantine 20 μM 預培養後處理 Aβ25-35，以流式細胞儀分析細胞凋亡、
細胞內鈣離子含量、活性氧物種及粒線體膜電位之改變，並利用西方點墨
法分析 cytochrome c 及 caspase 3 在細胞質中蛋白質表現，最後以即時定量
要
聚合酶連鎖反應觀察在微陣列中所發現高度表達之基因。結果發現以 50
(中)
μM Aβ25-35 處理 48 小時顯著增加細胞內鈣離子濃度、粒線體膜電位去
極化、cytochrome c 釋出，造成細胞程式凋亡和壞死。單獨葉酸補充 1000
μM 可降低 Aβ25-35 所誘發細胞鈣離子濃度上升，並降低粒線體膜電位
去極化、細胞程式凋亡和壞死，另外也促進與 neurogenesis 相關基因
Neurod1 和與突觸新生及形成相關基因 Cbln1 表達量增加。單獨 Memantine
投予降低 Aβ25-35 所誘發之粒線體膜電位去極化及使 Cbln1 表達量上升，
但未能降低細胞程式凋亡和壞死。葉酸補充 500 μM 合併 Memantine 投予
降低 Aβ25-35 所誘發之粒線體膜電位去極化、cytochrome c 釋出、抑制活
性氧物種生成，進而減少細胞程式凋亡。葉酸補充 1000 μM 合併
Memantine 投予降低 Aβ25-35 所誘發粒線體 cytochrome c 釋出、細胞程式
凋亡和壞死。綜合上述，500 μM 和 1000 μM 劑量葉酸補充可透過不同機
轉幫助 Memantine 降低神經細胞受 Aβ 之傷害並促進有助於神經功能之基
因表現，其結果提供一個新的 AD 臨床藥物與營養素搭配治療病患之參考
依據。
Memantine is an approved option clinical drug for the treatment of Alzheimer’s
disease (AD) with only moderate therapeutic effect. Folate supplementation was not
摘 associated to decrease risk of AD、yet mechanism are unclear. This study was to
investigate whether and how mechanism by which folate supplement or/and
要
Memantine protect against amyloid-β (Aβ)-induce neurotoxicity. Effects of folate
(英)
supplementation (8 mg/kg/day) on the brain of gene expression profile of Memantine
(30 mg/kg/day) -treated AD transgenic Tg2576 mice、were analysis using cDNA
microarrays. Expression data were analyzed using GeneSpring GX 10. Compared to
Memantine-treated Tg2576 mice brains、folate supplemental showed a generalized
up-regulation of 74 gene transcriptions involving in transcription factor complex、
hormone activity、cell growth and maintenance、signal transduction、brain
function. Using real-time PCR to confirmed up-regulated 2-6 fold gene expression、
example involving in neurogenesis (Neurod1)、cell growth and maintenance
(Fgf7)、synaptic formation/synaptogenesis (Car8、Cbln1 and Cbln3) and
neurotransmitter receptors (Slc6a2). To further study the mechanism using cell
culture of neuroblastoma cell line SH-SY5Y as the experiment model. SH-SY5Y
were pre-incubated 500 or 1000 μM folate 24hrs or 20 μM Memantine 3hrs
respectively and combination、and then treated Aβ25-35 48hrs. Aβ25-35 50 μM
was increased calcium influx、mitochondria membrane potential depolarization、
cytochrome c released to cytoplasm、apoptosis and necrosis. Folate 1000 μM
treatment of Aβ25-35-treated cells were decreased calcium influx、apoptosis and
necrosis、increased involving in neurogenesis gene Neurod1 expression and
involving in synaptic formation/synaptogenesis gene Cbln1 expression. Memantine
treatment of Aβ25-35-treated cells were decreased mitochondria membrane
potential depolarization、and Cbln1 expression was increased. Folate 500 μM
combined with Memantine treatment of Aβ25-35-treated cells were decreased
mitochondria membrane potential depolarization、reactive oxygen species、
cytochrome c released to cytoplasm and apoptosis. Folate 1000 μM combined with
Memantine treatment of Aβ25-35-treated cells were decreased cytochrome c
released to cytoplasm、apoptosis and necrosis. Taken together、our data
demonstrated that different dose of folate supplementation in combination with
Memantine may can protect against Aβ-induced SH-SY5Y cells neurotoxicity
through decrease ROS、mitochondria membrane potential depolarization、
cytochrome c released to cytoplasm、apoptosis or necrosis、and increase gene
expression involved neuron functions.
論
文
目
次
目錄 頁次 中文摘
要……………………………………………………………………I 英文摘
要………………………………………………………………….III 縮寫
表………………………………………………………………………V 致
謝……………………………………………………………………….XIII 表目
錄…………………………………………………………………….XIX 圖目
錄…………………………………………………………………….XX 第一
章、 前言…………………………………………………………….1 第二章、
文獻回顧……………………………………………………….2 一、 阿茲海默
症之病理機轉……………………………………….2 (一) 類澱粉蛋白之生
成………………………………………….2 (二) 類澱粉蛋白之神經毒
性…………………………………….4 1. 類澱粉蛋白引起之氧化壓
力………………………………………….4 2. 類澱粉蛋白引起細胞程式凋
亡……………………………………….5 3. Aβ25-35 與 Aβ1-42 所誘發之神
經毒性……………………………..7 (三)近年與 AD 微陣列研究相關基因之
表達……………………..9 二、 葉酸營養對於神經性退化疾病之風
險……………………….12 (一) 葉酸單碳代
謝…………………..………………………….12 (二) 葉酸營養與神經性退化
疾病之相關性……..…………….13 三、 葉酸營養降低阿茲海默症之分子機
轉……………………….15 (一) 葉酸之抗氧化能
力………………………………………….15 (二) 葉酸營養降低細胞程式凋亡
之能力……………………….17 (三) 葉酸營養調節類澱粉蛋白誘發之神經毒
性……………….18 四、 Memantine 藥理作用機
轉…………………………………….20 五、 研究動機與目
標……………………………………………….22 第三章、 實驗架構與材料
方法………………………………………….25 一、 實驗設
計……………………………………………………….25 二、 實驗材
料……………………………………………………….27 (一) 細胞
株……………………………………………………….27 (二) 培養液、試劑與
儀器設備………………………………….27 1. 培養
液………………………………………………………………….27 2. 試
劑…………………………………………………………………….28 3. 儀器設
備……………………………………………………………….29 三、 實驗方
法……………………………………………………….29 (一) 細胞培
養…………………………………………………….29 (二) 藥品之製
備………………………………………………….29 (三) 實驗動物腦組
織…………………………………………….30 (四) 反轉錄聚合酶連鎖反
應…………………………………….30 (五) 即時定量聚合酶連鎖反
應………………………………….33 (六) 細胞巨觀形態之觀
察……………………………………….34 (七) 功能性基因體微陣列分
析………………………………….34 (八) 細胞內游離鈣離子之分
析………………………………….36 (九) 細胞程式凋亡及壞死之分
析……………………………….36 (十) 細胞粒線體膜電位之測
定………………………………….37 (十一) 細胞內 ROS 之分
析……………………………………….38 (十二) 西方點墨法分
析………………………………………….39 四、 資料統計分
析………………………………………………….40 第四章、 結果Ⅰ……………………………………………………….41 一、 cDNA 微陣列晶
片取樣及敘述………………………………….41 二、 補充葉酸調節
Memantine 投予之 Tg2576 小鼠腦部基因表現量.43 第五章、 討論Ⅰ………………………………………………………….46 一、葉酸補充調
節之基因對於可能影響神經功能之分類與簡述……….46 (一) 與神經發育、
neurogenesis 和分化相關基因…………….46 (二) 與突觸新生與形成相關基
因………………………………….49 (三) 細胞生長與維持相關基
因…………………………………….50 (四) 與記憶學習能力相關基
因…………………………………….50 (五) 其他功
能……………………………………………………….51 二、葉酸補充調節
之基因與 AD 相關微陣列文獻比照…………………….52 三、與葉酸相關微
陣列文獻之基因比照………………………………….54 四、結
論…………………………………………………………………….55 第四
章、結果-Ⅱ…………………………………………………………..71 一、
Aβ25-35 處理對神經母細胞瘤細胞株 SH-SY5Y 形態上之改變及誘發 細胞
程式凋亡及壞死……………………………………………………….71 二、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 形態改變之影響………………………………………………….71 三、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 細胞程式凋亡之影響…………………………………………….72 四、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 細胞壞死之影響………………………………………………….72 五、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 細胞內鈣離子濃度之影響……………………………………….73 六、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 粒線體膜電位之影響…………………………………………….74 七、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 活性氧物種生成之影響………………………………………….74 八、
投予葉酸補充與 Memantine 後以 Aβ25-35 處理對神經母細胞瘤細胞株 SHSY5Y 細胞內 cytochrome c 與 caspase 3 蛋白質表現之影響…….75 九、以細
胞模式觀察葉酸補充並投予 Memantine 後處理 Aβ25-35 之基因表 達變
化……………………………………………………………………….76 第五
章、討論-Ⅱ…………………………………………………………..78 一、葉
酸補充與投予 Memantine 對神經母瘤細胞株受 Aβ 改變細胞內鈣 離子濃
度、ROS、粒線體膜電位及細胞程式凋亡之影響……………….78 二、葉酸
補充與投予 Memantine 改變受 Aβ 刺激之神經母瘤細胞株之基 因表達
量…………………………………………………………………….84 三、結
論…………………………………………………………………….85 第六
章、總結……………………………………………………………….86 第七
章、參考文獻………………………………………………………….104 表目
錄 表一、Memantine 與合併葉酸補充之 Tg2576 基因轉殖小鼠腦部正向調
控之基因變化……………………………………………………………….56
表二、Memantine 與合併葉酸補充之 Tg2576 基因轉殖小鼠腦部負向 調控之
基因變化…………………………………………………….61 表三、
Memantine 與合併葉酸補充之 Tg2576 基因轉殖小鼠腦部轉錄 因子複合體及
與荷爾蒙活性相關之基因改變…………………….62 表四、Memantine 與合
併葉酸補充之 Tg2576 基因轉殖小鼠腦部細胞 生長與維持及訊息傳遞相關
之基因改變………………………….63 表五、Memantine 與合併葉酸補充之
Tg2576 基因轉殖小鼠腦部其腦 部功能、細胞自我程式凋亡及免疫反應相關
之基因改變……….64 表六、葉酸補充與投予 Memantine 降低 Aβ 對 SHSY5Y 細胞之傷害 及調節基因表達之總
論…………………………………………….87 附表一、即時定量聚合酶連
鎖反應引子與探針 (人類) ……………….127 附表二、即時定量聚合酶連鎖
反應引子與探針 (小鼠) ……………….128 附表三、細胞培養材
料…………………………………………………….129 附表四、實驗分析藥
劑與材料…………………………………………….130 附表五、儀器設備與
編號………………………………………………….132 圖目錄 圖一、微陣列
分析之晶片影像圖………………………………………….65 圖二、微陣列
分析晶片上之螢光訊號強度圖…………………………….66 圖三、微陣列
分析晶片上之螢光訊號圖………………………………….67 圖四、微陣列
分析晶片之品質控管……………………………………….68 圖五、由原始
微陣列資料所得與轉錄因子和賀爾蒙活性相關為主之基 因其生物性及功能
性之交互作用………………………………….69 圖六、以即時定量 PCR 確
認基因微陣列之基因表達…………………….70 圖七、不同濃度 Aβ25-35
處理對 SH-SY5Y 細胞株誘發細胞型態改變之 影
響………………………………………………………………….88 圖八、不
同濃度 Aβ25-35 處理對 SH-SY5Y 細胞株誘發細胞死亡之影響.89 圖九、葉
酸補充、Memantine 處理與合併補充下對 Aβ25-35 處理 SH-SY5Y 細胞株引
起細胞型態改變之影響……………………….90 圖十、葉酸補充、
Memantine 處理與合併補充下對 Aβ25-35 處理 SH-SY5Y 細胞株引起細胞自
我程式凋亡之影響………………….91 圖十一、葉酸補充、Memantine 處理
與合併補充下對 Aβ25-35 處理 SH-SY5Y 細胞株引起細胞壞死之影
響………………………….92 圖十二、葉酸補充、Memantine 處理與合併補
充下對 Aβ25-35 處理 SH-SY5Y 細胞株對細胞內鈣離子濃度之影
響………………….93 圖十三、葉酸補充、Memantine 處理與合併補充下對
Aβ25-35 處理 SH-SY5Y 細胞株對粒線體膜電位之影
響……………………….94 圖十四、葉酸補充、Memantine 處理與合併補充
下對 Aβ25-35 處理 SH-SY5Y 細胞株對活性氧物種之影
響………………………….95 圖十五、葉酸補充、Memantine 處理與合併補
充下對 Aβ25-35 處理 SH-SY5Y 細胞株對 Cytochrome c 蛋白質表現之影
響……….96 圖十六、葉酸補充、Memantine 處理與合併補充下對 Aβ25-35
處理 SH-SY5Y 細胞株對 Pro-caspase 3 蛋白質表現之影響…….97 圖十七、
葉酸補充、Memantine 處理與合併補充下對 Aβ25-35 處理 SH-SY5Y 細胞株
對 Fgf7 基因表現之影響…………………….98 圖十八、葉酸補充、
Memantine 處理與合併補充下對 Aβ25-35 處理 SH-SY5Y 細胞株對 Slc6a2 基
因表現之影響………………….99 圖十九、葉酸補充、Memantine 處理與合
併補充下對 Aβ25-35 處理 SH-SY5Y 細胞株對 Neurod1 基因表現之影
響……………….100 圖二十、葉酸補充、Memantine 處理與合併補充下對
Aβ25-35 處理 SH-SY5Y 細胞株對 Car8 基因表現之影
響…………………….101 圖二十一、葉酸補充、Memantine 處理與合併補充
下對 Aβ25-35 處理 SH-SY5Y 細胞株對 Cbln1 基因表現之影
響……………….102 圖二十二、葉酸補充、Memantine 處理與合併補充下對
Aβ25-35 處理 SH-SY5Y 胞株對 Cbln3 基因表現之影響………………….103
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