臺灣博碩士論文加值系統

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 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 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 Memantine protect against amyloid-β (Aβ)-induce neurotoxicity. Effects of folate 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.

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
SH-SY5Y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
SH-SY5Y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
SH-SY5Y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
SH-SY5Y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
SH-SY5Y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
SH-SY5Y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
SH-SY5Y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SH-SY5Y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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