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研究生:盧瑋翎
研究生(外文):Lu Wei Ling
論文名稱:在乙型澱粉樣蛋白中探討二十二碳六烯酸和奈米金對於N2A細胞之影響
論文名稱(外文):Effect of Docosahexaenoic acid and AuNPs in N2A cells with Aβ
指導教授:江明璋
指導教授(外文):Chiang MingChang
口試委員:李憶菁鄭邑荃
口試日期:2015-07-20
學位類別:碩士
校院名稱:輔仁大學
系所名稱:生命科學系碩士班
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:134
中文關鍵詞:阿茲海默症神經瘤母細胞乙型澱粉樣蛋白二十二碳六烯酸奈米金
外文關鍵詞:Alzheimer diseaseN2A cellAmyloid β(1-42)DHA,AuNPs
相關次數:
  • 被引用被引用:2
  • 點閱點閱:140
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  • 下載下載:4
  • 收藏至我的研究室書目清單書目收藏:0
阿茲海默症(Alzheimer disease, AD)是最常見的失智症(dementia)類型(60%~80%),是與老化相關的神經退行性疾病。AD的特徵是記憶和認知的喪失、腦萎縮、乙型澱粉樣蛋白(Beta Amyloid, Aβ)斑塊(plaques)的積聚和神經原纖維(Neurofibrillary tangle)糾結。然而,斑塊主要是由Aβ在神經周圍堆積形成(發現在阿茲海默症患者發現的細胞外沉積物)。有研究指出,補充二十二碳六烯酸(Docosahexaenoic acid, DHA)顯著降低Aβ的毒性,可能具有神經保護潛力。另外,奈米金(AuNPs),一種新穎的物質,具有良好的生物相容性,在生物醫學研究具有科學應用潛力。研究指出奈米金可以促進N2A細胞的神經突觸增生,神經突觸長度的顯著增加可以做為神經分化的指標。另外的文獻也指出同樣為神經病變疾病的亨丁頓舞蹈症在N2A細胞模型下給予AuNPs,可以減少mHtt (突變亨丁頓蛋白)聚集。本研究使用Amyloid β(1-42)誘導小鼠神經瘤母細胞(Neuro-2a cell, N2A)死亡,模擬AD模型,並在細胞中分別加入DHA和AuNPs。我們利用MTT assay和Live/Dead dye kit評估了Aβ、DHA和AuNPs對於N2A細胞的作用。MTT結果顯示,N2A細胞經過2.5M A(1-42) 處理72小時,細胞存活率顯著減少。給予5 M DHA對於細胞毒性測試而言可能使N2A細胞免受Aβ毒性影響。給予5 ppm AuNPs對於細胞毒性測試而言不能使N2A細胞免受Aβ毒性影響。Live/Dead dye kit結果顯示,給予5 M DHA或5 ppm AuNPs在Aβ的毒性下,相較Aβ的組別細胞存活率沒有差異。點子顯微鏡的結果顯示,不論是物理或化學製程的奈米金都可以透過細胞膜進入N2A細胞內。我們發現,Aβ的毒性會使N2A細胞內的大部分線粒體皺縮壞死。給予Aβ合併物理或化學製程的奈米金並沒有改善線粒體皺縮壞死的情況。Microarray分析結果指出處理Aβ的組別與控制組相比有78個基因表現量上升,144個基因表現量下降。在Aβ的作用下,處理DHA的組別與控制組相比有390個基因表現量下降,355個基因表現量上升;處理AuNPs的組別與控制組相比有836個基因表現量下降,525個基因表現量上升。為了進一步了解,我們將使用QPCR和Western blot,來確認相關基因和蛋白質的關係。這些研究結果將擴展我們對於DHA和AuNPs於Aβ所造成的相關神經元損傷之核心作用,在神經退行性疾病有更多的了解。
Alzheimer disease (AD) is a primary type of dementia (60%–80%) and the most prevalent neurodegenerative disorder associated with aging. AD is characterized by progressive loss of memory and cognition, brain atrophy, and accumulation of amyloid plaques and neurofibrillary tangle. However, amyloid beta peptide (Aβ) is the main component of amyloid plaques (extracellular deposits found in the brains of patients with AD). In some studies show that Docosahexaenoic acid (DHA) supplementation caused a significant reduction in Aβ toxic that may have neuroprotection potential. Gold nanoparticles (AuNPs) a novel agent, has good biocompatibility and has been used in biomedical researches. Investigations suggest AuNPs can promote neurite outgrowth of N2A cells and significantly increase the neurite length that can be used as the index of differentiation potential. Recent studies suggested that AuNPs reduced mHtt aggregates in mHtt expressing (Huntington disease, HD) N2A cells. We used the toxin, Aβ, triggered N2A cell as model of AD. DHA and AuNPs were treated to cells respectively. We assessed the effects of Aβ, DHA and AuNPs on cell viability and Live/Dead dye kit in N2A cells. The result of MTT assay, N2A cells were treated with 2.5 M A(1-42) for 72 h, and cell viability was reduced significantly in A by MTT assay. Treatment of 5 M DHA may protect N2A cells from Aβ toxicity in cell viability. Treatment of 5 ppm AuNPs do not protect N2A cells from Aβ toxicity in cell viability. Live/Dead dye activity was detected after A treatment for 72 h, and was significantly different by A. The result of Live/Dead kit showed that treated with the 5M DHA or 5 ppm AuNPs from Aβ toxicity independently, the cell viability has no significant difference compared with 2.5 M Aβ. Microarray analysis was to compare the effect of Aβ with DHA and AuNPs related gene expression in N2A cells. The results showed that 78 genes were up regulated and 144 genes were down regulated in the Aβ trial when compared to the control trial. We confirmed the AuNPs (chemical and physical)can go through the cell membrane inside the N2A cells. The result of Transmission Electron Microscopy, we found that the average mitochondrial was shrinkage necrosis in N2A cells from Aβ toxicity. Treatment of AuNPs (chemical and physical) also made average mitochondrial shrinkage necrosis in N2A cells from Aβ toxicity. The DHA with Aβ trial showed that 390 genes were up-regulated and 355 genes were down-regulated compared to the control trial. The AuNPs with Aβ trial showed that 836 genes were up-regulated and 525 genes were down-regulated compared to the control trial. To extending our understanding, we will use QPCR and Western blot to confirm related gene and protein. Our findings will extend our understanding of the central role of DHA and AuNPs in Aβ-related neuronal impairment, which probably increase risks in neurodegenerative diseases.
Abstract I
摘要 III
誌謝 V
目錄 VII
表、圖目錄 XII
第一章 緒論 1
1.1阿茲海默症 1
1.1乙型澱粉樣蛋白 2
1.2 二十二碳六烯酸 3
1.3 奈米金 4
第二章 研究前言與目的 5
第三章 實驗材料與方法 6
3.1 細胞株 (cell line) 6
3.2 細胞培養 (cell culture) 6
3.3 細胞計數 (cell number) 7
3.4 細胞模式 (cell model)的建立 7
3.4-1 細胞Amyloid β(1-42)處理 8
3.4-2 細胞DHA處理 8
3.4-3細胞AuNPs處理 8
3.5 細胞活性分析 8
3.5-1 MTT assay 8
3.5-2 Live/Dead assay 9
3.6 Whole Genome Onearray 10
3.6-1 Total RNA 萃取 10
3.6-2 Human Oligonucleotide DNA microarray (HOA) 10
3.6-3 Microarray 10
3.6-4結果分析 11
3.7蛋白質分析 11
3.7-1 蛋白質萃取與定量 11
3.7-2 SDS polyacrylamide膠體電泳 (SDS-PSGE) 12
3.7-3 西方墨點法 (Western blot) 13
3.8定量聚合酶連鎖反應 (Real-time quantitative polymerase chain reaction, Q-PCR) 14
3.8-1 RNA萃取與反轉錄cDNA 14
3.8-2定量聚合酶連鎖反應 15
3.9 穿透式電子顯微鏡 (Transmission electron microscopy) 15
3.10統計方式/軟體 17
第四章 實驗結果 18
4.1 觀察給予不同濃度Amyloid β(1-42)、DHA及AuNPs處理後,對於N2A細胞株存活率影響 18
4.1-1給予不同濃度Amyloid β(1-42) (1, 2.5, 5, 10, 20 μM)處理72小時後,對於N2A細胞株存活率影響 18
4.1-2給予不同濃度DHA (1, 5, 10, 20 μM)處理72小時後,對於N2A細胞株存活率影響 18
4.1-3給予不同濃度AuNPs (1, 5, 10, 20 ppm)處理72小時後,對於N2A細胞株存活率影響 19
4.2 觀察給予Amyloid β(1-42)及DHA處理後,對於N2A細胞株存活率影響 19
4.3 觀察給予Amyloid β(1-42)及AuNPs處理後,對於N2A細胞株存活率影響 20
4.4 觀察給予Amyloid β(1-42)及AuNPs處理後,對於N2A細胞株粒線體的影響 20
4.5比較N2A細胞株,經Amyloid β(1-42) 、DHA及AuNPs處理後,PSEN1基因表現 21
4.6比較N2A細胞株,經Amyloid β(1-42)、DHA及AuNPs處理後,PSEN1蛋白質表現 21
4.7比較N2A細胞株,經Amyloid β(1-42)、DHA及AuNPs處理後,CREB蛋白質表現 22
4.8比較N2A細胞株,經Amyloid β(1-42)、DHA及AuNPs處理後,Bcl-2蛋白質表現 22
4.9比較N2A細胞株,經Amyloid β(1-42)、DHA及AuNPs處理後,經由Whole Genome OneArray® (HOA )分析基因表現 22
第五章 討論 25
5.1觀察給予Amyloid β(1-42) 、DHA及AuNPs處理後,對於N2A細胞株存活率影響 25
5.2比較N2A細胞株,經Amyloid β(1-42)及AuNPs處理後,粒線體的影響 26
5.3比較N2A細胞株,經Amyloid β(1-42)、DHA及AuNPs處理後,PSEN1基因與蛋白質表現 26
5.4比較N2A細胞株,經Amyloid β(1-42) 、DHA及AuNPs處理後,CREB蛋白質表現 27
5.5比較N2A細胞株,經Amyloid β(1-42) 、DHA及AuNPs處理後,BCL-2蛋白質表現 28
5.6比較N2A細胞株,經Amyloid β(1-42) 、DHA及AuNPs處理後,經由Whole Genome OneArray® (HOA )分析基因表現 28
第六章 未來展望 33
第七章 圖、表及說明 34
第八章 參考文獻 68
附錄 80

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