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研究生:王修筠
研究生(外文):Hsiu-Yun Wang
論文名稱:β-hydroxybutyrate 對於由葡萄糖缺乏所誘發之 SH-SY5Y 細胞中 Aβ 含量及自噬作用之影響
論文名稱(外文):Effects of β-hydroxybutyrate on autophagy and Aβ in SH-SY5Y cells under glucose depleted condition
指導教授:林士祥
指導教授(外文):Shyh-Hsiang Lin
口試委員:邱琬淳沈賜川
口試委員(外文):Wan-Chun ChiuSzu-Chuan Shen
口試日期:2017-07-12
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:保健營養學研究所
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:70
中文關鍵詞:葡萄糖缺乏β-類澱粉蛋白自噬作用β-羥基丁酸
外文關鍵詞:glucose deprivationβ-amyloid (Aβ)autophagyβ-hydroxybutyrate (BHB)
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背景:葡萄糖為腦部主要能量來源,當葡萄糖缺乏時會造成 reactive oxygen species (ROS) 生成與粒線體功能異常,導致β-amyloid (Aβ) 產生,而酮體在缺乏葡萄糖時可作為腦部能量來源。自噬作用為細胞營養缺乏下分解有害蛋白並提供能量的保護機制,被認為可以減少Aβ並扮演保護神經的角色。酮體可降低Akt/mTOR signaling 促進自噬作用,支持電子傳遞鏈正常運作以減少 ROS 生成,刺激自噬體分解,加速 Autophagic flux 以避免自噬體堆積造成細胞死亡。目的:探討β-hydroxybutyrate (BHB) 是否可調節人類神經纖維瘤母細胞株 SH-SY5Y 細胞自噬作用以清除因葡萄糖缺乏而產生的Aβ並減少細胞死亡。材料方法:研究以 Retinoic acid (RA) 分化 SH-SY5Y細胞後,加入BHB於無葡萄糖培養基中培養 24 小時,檢測細胞存活率並觀察Akt/mTOR signaling、自噬作用相關蛋白及Aβ之表現。結果:葡萄糖缺乏下會降低p-Akt/Akt、p-mTOR/mTOR,提高LC3-II/LC3-I、Aβ含量並降低細胞存活率。在葡萄糖缺乏下介入不同濃度BHB與無葡萄糖組相比,p-Akt/Akt、p-mTOR/mTOR、LC3-II/LC3-I、Aβ及細胞存活率並不受影響,而在12 mM BHB介入下 p62 表現會提升。結論:BHB降低Akt/mTOR signaling及增加自噬體形成的影響可能與無葡萄糖組重疊,且由於SH-SY5Y細胞缺乏succinyl-CoA:3-ketoacid CoA transferase (SCOT) 使其無法利用酮體產能,造成自噬體堆積使p62上升、Aβ增加與細胞死亡。
Background:Glucose is the major energy substrate in brain. Glucose deprivation will cause the production of ROS and mitochondrial dysfunction, leading to generate Aβ. Ketone bodies can substitute for glucose. Autophagy can solve damage proteins and supply energy in nutrient depletion, and be thought to reduce Aβ and protect neurons. Ketone bodies can attenuate Akt/mTOR signaling to promote autophagy, support electron transfer chain to decrease ROS production, and stimulate autophagic flux to reduce cell death. Purpose:To investigate whether BHB can regulate SH-SY5Y cell autophagy to scavenge Aβ generated by glucose deprivation and reduce the cell death. Methods:After cell differentiation by RA, SH-SY5Y cells were treated with BHB for 24 hours, and then tested cell viability, Akt/mTOR signaling, autophagy related proteins and Aβ expression. Results:Glucose deprivation decreased p-Akt/Akt, p-mTOR/mTOR and cell viability, and increased LC3-II/LC3-I and Aβ. Compared to glucose free group, the groups treated with different concentration of BHB shows no difference in p-Akt/Akt, p-mTOR/mTOR, LC3-II/LC3-I, Aβ and cell viability, but increased p62 in 12 mM BHB group. Conclusion:BHB might has the same condition of glucose deprivation decreasing Akt/mTOR signaling and increasing autophagosome. Due to the absence of SCOT, SH-SY5Y cells are blocked ketone bodies utilization, causing increase of autophagosome, p62, Aβ and cell death
目錄
頁數
中文摘要 I
英文摘要 II
致謝 III
目錄 V
表目次 VII
圖目次 VIII
第一章 緒論 1
第二章 文獻回顧 3
第一節 神經退化性疾病 (Neurodegenerative disease, NDs) 3
一、神經退化性疾病 3
二、阿茲海默症 (Alzheimer’s disease, AD) 流行病學 3
三、阿茲海默症病因機制 4
四、Aβ之毒性 (toxicity) 6
第二節 自噬作用 (Autophagy) 8
一、自噬作用 8
二、Macroautophagy 9
三、自噬作用與神經退化性疾病 11
第三節 細胞凋亡 (Apoptosis) 14
第四節 酮體 (Ketone bodies) 15
一、生酮飲食 (Ketogenic diet, KD) 15
二、酮體與阿茲海默症 16
三、酮體與自噬作用 18
第三章 材料與方法 23
第一節 實驗設計 23
第二節 細胞培養 25
一、人類神經纖維瘤母細胞 (Human neuroblastoma cell line, SH-SY5Y) 25
二、DMEM/F12 培養基 25
三、細胞分化 (cell differentiation) 25
四、細胞繼代 26
五、細胞凍存 26
第三節 RA的製備 27
一、RA原液製備 27
二、給予濃度或時間 27
第四節 DL-β-Hydroxybutyrate的製備 28
一、DL-β-Hydroxybutyrate製備 28
二、給予濃度或時間 28
第五節 細胞存活率分析 29
一、實驗原理 29
二、實驗步驟 29
第六節 西方點墨法 (Western blotting) 30
一、實驗原理 30
二、實驗材料 30
三、實驗步驟 30
統計分析 35
第四章 結果 36
第一節 未分化與分化後之細胞型態與分化指標 36
一、細胞型態 36
二、分化指標 NeuN蛋白質表現量 36
第二節 NaBHB對於細胞存活率之影響 37
第三節 NaBHB在葡萄糖缺乏下對於細胞型態與細胞存活率之影響 38
一、細胞型態 38
二、細胞存活率 38
第四節 NaBHB在葡萄糖缺乏下對於p-Akt/Akt與自噬作用相關蛋白質表現量之影響 39
一、p-Akt/Akt蛋白質表現量 39
二、p-mTOR/mTOR蛋白質表現量 39
三、LC3-II/LC3-I蛋白質表現量 40
四、p62蛋白質表現量 40
第五節 NaBHB在葡萄糖缺乏下對於Aβ蛋白質表現量之影響 41
第五章 討論 42
第一節 NaBHB 在葡萄糖缺乏下對於 Akt/mTOR signaling 之影響 42
第二節 NaBHB在葡萄糖缺乏下對於自噬作用之影響 44
第三節 NaBHB在葡萄糖缺乏下對於Aβ 之影響 46
第四節 NaBHB在葡萄糖缺乏下對於細胞存活率之影響 48
第六章 總結 50
參考文獻 51


表目次
Table 1. Lysis buffer 32
Table 2. SDS-PAGE gel 32
Table 3. 1X SDS-PAGE Running buffer 33
Table 4. 1X Transfer buffer 33
Table 5. 1X TBS buffer 34
Table 6. 1X TBST buffer 34
Table 7. Blocking buffer 34


圖目次
圖一、APP分解途徑與Aβ之形成 6
圖二、Aβ毒性對細胞之影響 7
圖三、自噬作用路徑 9
圖四、類泛素修飾作用與自噬體形成 11
圖五、實驗一流程圖 23
圖六、實驗二流程圖 24
圖七、β-hydroxybutyrate與 DL-β-Hydroxybutyric acid sodium salt 之結構 28
圖八、以10 μM RA介入對於細胞型態之影響 61
圖九、以10 μM RA介入對於細胞分化指標NeuN蛋白質表現量之影響 62
圖十、不同濃度NaBHB對於細胞存活率之影響 63
圖十一、不同濃度NaBHB於無葡萄糖培養基介入24小時對於細胞型態之影響 64
圖十二、不同濃度NaBHB於無葡萄糖培養基介入24小時對於細胞存活率之影響 65
圖十三、不同濃度NaBHB於無葡萄糖培養基介入24小時對於p-Akt/Akt蛋白質表現量之影響 66
圖十四、不同濃度NaBHB於無葡萄糖培養基介入24小時對於p-mTOR/mTOR蛋白質表現量之影響 67
圖十五、不同濃度NaBHB於無葡萄糖培養基介入24小時對於LC3-II/LC3-I蛋白質表現量之影響 68
圖十六、不同濃度NaBHB於無葡萄糖培養基介入24小時對於p62蛋白質表現量之影響 69
圖十七、不同濃度NaBHB於無葡萄糖培養基介入24小時對於Aβ蛋白質表現量之影響 70
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