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題名 半乳糖凝集素-3促進乙型類澱粉蛋白寡聚合作用
Galectin-3 facilitates amyloid-beta oligomerization作者 鄭光閔
Zheng, Kuang Min貢獻者 李小媛<br>趙知章
Lee, Eminy H.Y.<br>Chao, Chih Chang
鄭光閔
Zheng, Kuang Min關鍵詞 半乳糖凝集素-3
乙型類澱粉蛋白
寡聚合作用
腦啡肽酶
PIAS1
APP/PS1基因轉殖小鼠
Galectin-3
Aβ
Oligomerization
Neprilysin
PIAS1
APP/PS1 transgenic mice日期 2017 上傳時間 13-Sep-2017 14:49:49 (UTC+8) 摘要 阿茲海默症是一種隨著年齡老化有關的神經退化性疾病，其特徵主要為記憶喪失及認知功能失調。阿茲海默症有兩個主要的病理指標，包含了因為濤蛋白造成的神經纖維糾結以及乙型類澱粉蛋白堆積而成的老化斑塊。乙型類澱粉蛋白是由類澱粉前驅蛋白經β-分泌酶及γ-分泌酶連續裁切生成大小約4-kDa的胜肽。乙型類澱粉蛋白會相互堆積形成寡聚體，並且高分子量寡聚體進一步再堆積成不可溶性的乙型類澱粉蛋白纖維及老化斑塊。半乳糖凝集素-3是半乳糖凝集素家族的一員，目前已知半乳糖凝集素-3調節各種細胞的功能，例如發炎、腫瘤生長以及細胞間的黏附，而在癌症中則有促使癌細胞積聚的能力，然而在大腦中的作用仍尚不清楚。在本研究中，我們使用APP/PS1基因轉殖小鼠作為阿茲海默症的動物模型，並且在其大腦中研究半乳糖凝集素-3對於乙型類澱粉蛋白堆積的作用與機制。結果顯示在野生型小鼠的海馬迴中過度表現半乳糖凝集素-3會促進乙型類澱粉蛋白的堆積，而將乙型類澱粉蛋白注射在半乳糖凝集素-3基因剔除小鼠的海馬迴，則會觀察到乙型類澱粉蛋白寡聚合作用的減少。乙型類澱粉蛋白的注射也會增加海馬迴中半乳糖凝集素-3的表現。在APP/PS1小鼠的海馬迴可以觀察到半乳糖凝集素-3的表現量會隨著年齡增長而增加，而具有抑制發炎及免疫反應的PIAS1在APP/PS1小鼠海馬迴中的表現量則會隨著年齡增長而減少。在探討半乳糖凝集素-3調節乙型類澱粉蛋白寡具體作用的過程中，我們發現半乳糖凝集素-3基因剔除小鼠的海馬迴中能夠代謝乙型類澱粉蛋白的腦啡肽酶表現量是野生型小鼠的兩倍多。研究結果顯示半乳糖凝集素-3對於乙型類澱粉蛋白的堆積扮演了重要的角色以及可能在阿茲海默症的病理機制中具有重要的作用。
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder which is characterized by progressive loss of memory and other cognitive functions. The two pathological hallmarks of AD are extracellular amyloid plaque and flame-shaped neurofibrillary tangles of the tau protein. Aβ is a 4-kDa protein that is resulted from sequential cleavage of the amyloid precursor protein by beta-secretase and gamma-secretase. Once Aβ is produced, it will aggregate to form oligomers and high molecular weight (HMW) oligomers will further assemble to form large insoluble fibrils and plaque. Galectin-3 (Gal-3) is a member of the β-galactoside-binding galectin protein family. Gal-3 is known to regulate various cellular functions, such as inflammation, tumor progression and cell-cell adhesion. In cancer cell, Gal-3 enhances homotypic aggregation, but its role in the brain is much less known. In the present study, we examined the role and mechanism of Gal-3 in Aβ aggregation in the brain by adopting the APP/PS1 mice as an animal model of AD. Results revealed that overexpression of Gal-3 enhanced Aβ oligomerization, whereas Aβ injection into hippocampus of Gal-3 KO mice reduced Aβ oligomerization. Aβ injection also increased Gal-3 expression in the hippocampus. Gal-3 expression is also increased in APP/PS1 mice and this effect is more significant along with ageing. Meanwhile, the expression of protein inhibitor of activated STAT1 (PIAS1) that suppresses inflammation and immune response was decreased with ageing in APP/PS1 mice. We further found that the expression level of neprilysin, an enzyme that degrades Aβ, was increased for approximately two-folds in Gal-3 KO mice compared with WT mice. 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Proceedings of the National Academy of Sciences of the United States of America 72:1858-1862.Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harbor perspectives in medicine 2(1):a006346.Yan YP, Lang BT, Vemuganti R, Dempsey RJ (2009) Galectin-3 mediates post-ischemic tissue remodeling. Brain research 1288:116-124.Zhao Q, Barclay M, Hilkens J, Guo X, Barrow H, Rhodes JM, Yu LG (2010) Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Molecular cancer 9:154. 描述 碩士
國立政治大學
神經科學研究所
104754005資料來源 http://thesis.lib.nccu.edu.tw/record/#G0104754005 資料類型 thesis dc.contributor.advisor 李小媛<br>趙知章 zh_TW dc.contributor.advisor Lee, Eminy H.Y.<br>Chao, Chih Chang en_US dc.contributor.author (Authors) 鄭光閔 zh_TW dc.contributor.author (Authors) Zheng, Kuang Min en_US dc.creator (作者) 鄭光閔 zh_TW dc.creator (作者) Zheng, Kuang Min en_US dc.date (日期) 2017 en_US dc.date.accessioned 13-Sep-2017 14:49:49 (UTC+8) - dc.date.available 13-Sep-2017 14:49:49 (UTC+8) - dc.date.issued (上傳時間) 13-Sep-2017 14:49:49 (UTC+8) - dc.identifier (Other Identifiers) G0104754005 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/112681 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 104754005 zh_TW dc.description.abstract (摘要) 阿茲海默症是一種隨著年齡老化有關的神經退化性疾病，其特徵主要為記憶喪失及認知功能失調。阿茲海默症有兩個主要的病理指標，包含了因為濤蛋白造成的神經纖維糾結以及乙型類澱粉蛋白堆積而成的老化斑塊。乙型類澱粉蛋白是由類澱粉前驅蛋白經β-分泌酶及γ-分泌酶連續裁切生成大小約4-kDa的胜肽。乙型類澱粉蛋白會相互堆積形成寡聚體，並且高分子量寡聚體進一步再堆積成不可溶性的乙型類澱粉蛋白纖維及老化斑塊。半乳糖凝集素-3是半乳糖凝集素家族的一員，目前已知半乳糖凝集素-3調節各種細胞的功能，例如發炎、腫瘤生長以及細胞間的黏附，而在癌症中則有促使癌細胞積聚的能力，然而在大腦中的作用仍尚不清楚。在本研究中，我們使用APP/PS1基因轉殖小鼠作為阿茲海默症的動物模型，並且在其大腦中研究半乳糖凝集素-3對於乙型類澱粉蛋白堆積的作用與機制。結果顯示在野生型小鼠的海馬迴中過度表現半乳糖凝集素-3會促進乙型類澱粉蛋白的堆積，而將乙型類澱粉蛋白注射在半乳糖凝集素-3基因剔除小鼠的海馬迴，則會觀察到乙型類澱粉蛋白寡聚合作用的減少。乙型類澱粉蛋白的注射也會增加海馬迴中半乳糖凝集素-3的表現。在APP/PS1小鼠的海馬迴可以觀察到半乳糖凝集素-3的表現量會隨著年齡增長而增加，而具有抑制發炎及免疫反應的PIAS1在APP/PS1小鼠海馬迴中的表現量則會隨著年齡增長而減少。在探討半乳糖凝集素-3調節乙型類澱粉蛋白寡具體作用的過程中，我們發現半乳糖凝集素-3基因剔除小鼠的海馬迴中能夠代謝乙型類澱粉蛋白的腦啡肽酶表現量是野生型小鼠的兩倍多。研究結果顯示半乳糖凝集素-3對於乙型類澱粉蛋白的堆積扮演了重要的角色以及可能在阿茲海默症的病理機制中具有重要的作用。 zh_TW dc.description.abstract (摘要) Alzheimer’s disease (AD) is an age-related neurodegenerative disorder which is characterized by progressive loss of memory and other cognitive functions. The two pathological hallmarks of AD are extracellular amyloid plaque and flame-shaped neurofibrillary tangles of the tau protein. Aβ is a 4-kDa protein that is resulted from sequential cleavage of the amyloid precursor protein by beta-secretase and gamma-secretase. Once Aβ is produced, it will aggregate to form oligomers and high molecular weight (HMW) oligomers will further assemble to form large insoluble fibrils and plaque. Galectin-3 (Gal-3) is a member of the β-galactoside-binding galectin protein family. Gal-3 is known to regulate various cellular functions, such as inflammation, tumor progression and cell-cell adhesion. In cancer cell, Gal-3 enhances homotypic aggregation, but its role in the brain is much less known. In the present study, we examined the role and mechanism of Gal-3 in Aβ aggregation in the brain by adopting the APP/PS1 mice as an animal model of AD. Results revealed that overexpression of Gal-3 enhanced Aβ oligomerization, whereas Aβ injection into hippocampus of Gal-3 KO mice reduced Aβ oligomerization. Aβ injection also increased Gal-3 expression in the hippocampus. Gal-3 expression is also increased in APP/PS1 mice and this effect is more significant along with ageing. Meanwhile, the expression of protein inhibitor of activated STAT1 (PIAS1) that suppresses inflammation and immune response was decreased with ageing in APP/PS1 mice. We further found that the expression level of neprilysin, an enzyme that degrades Aβ, was increased for approximately two-folds in Gal-3 KO mice compared with WT mice. These results suggest that Gal-3 plays an important role in Aβ aggregation and possibly in the pathology of AD. en_US dc.description.tableofcontents 緒論 1一、 阿茲海默症 1二、 類澱粉前驅蛋白 3三、 乙型類澱粉蛋白 4四、 半乳糖凝集素 7五、 半乳糖凝集素-3 9六、 Protein inhibitor of activated STAT 1 (PIAS1) 12七、 實驗目的 13材料與方法 14一、 動物實驗與飼養 14二、 實驗動物基因型鑑定 15三、 海馬迴及前額葉皮質組織分離 16四、 蛋白質均質液置備 16五、 蛋白質濃度測定 17六、 西方墨點法 17七、 免疫共沉澱法 20八、 質體建構 20九、 轉型作用 21十、 大量質體DNA製備 22十一、 藥物與質體DNA製備及動物海馬迴內注射 23十二、 免疫螢光染色 24十三、 統計分析 25結果 26一、 乙型類澱粉蛋白急性刺激後48小時為最適宜觀察其寡聚合作用的時間點 26二、 不表現半乳糖凝集素-3減緩乙型類澱粉蛋白的寡聚合作用 29三、 過度表現半乳糖凝集素-3促進乙型類澱粉蛋白的寡聚合作用 33四、 海馬迴中乙型類澱粉蛋白的寡聚合作用隨著年齡增長而增加 36五、 大腦皮質前葉中的乙型類澱粉蛋白寡聚合作用也會隨著年齡增長而增加 39六、 隨著APP/PS1小鼠的年齡增加，半乳糖凝集素-3的表現也隨之增加，但PIAS1的表現則減少 42七、 半乳糖凝集素-3及PIAS1在正常生理狀態下其表現量不因年齡增長而改變 46八、 半乳糖凝集素-3與類澱粉前驅蛋白及乙型類澱粉蛋白會交互作用 48九、 半乳糖凝集素-3基因剔除小鼠其海馬迴中使代謝乙型類澱粉蛋白的腦啡肽酶表現量增加 50十、 在小鼠海馬迴中半乳糖凝集素-3的表現位置與Iba-1相同 53討論 55結論 63參考文獻 64 zh_TW dc.format.extent 1325317 bytes - dc.format.mimetype application/pdf - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0104754005 en_US dc.subject (關鍵詞) 半乳糖凝集素-3 zh_TW dc.subject (關鍵詞) 乙型類澱粉蛋白 zh_TW dc.subject (關鍵詞) 寡聚合作用 zh_TW dc.subject (關鍵詞) 腦啡肽酶 zh_TW dc.subject (關鍵詞) PIAS1 zh_TW dc.subject (關鍵詞) APP/PS1基因轉殖小鼠 zh_TW dc.subject (關鍵詞) Galectin-3 en_US dc.subject (關鍵詞) Aβ en_US dc.subject (關鍵詞) Oligomerization en_US dc.subject (關鍵詞) Neprilysin en_US dc.subject (關鍵詞) PIAS1 en_US dc.subject (關鍵詞) APP/PS1 transgenic mice en_US dc.title (題名) 半乳糖凝集素-3促進乙型類澱粉蛋白寡聚合作用 zh_TW dc.title (題名) Galectin-3 facilitates amyloid-beta oligomerization en_US dc.type (資料類型) thesis en_US dc.relation.reference (參考文獻) Abdallah B, Hassan A, Benoist C, Goula D, Behr JP, Demeneix BA (1996) A powerful nonviral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine. 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