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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 廖永豐 | |
dc.contributor.author | Ju-Yun Chou | en |
dc.contributor.author | 周儒筠 | zh_TW |
dc.date.accessioned | 2021-05-19T17:45:12Z | - |
dc.date.available | 2023-08-15 | |
dc.date.available | 2021-05-19T17:45:12Z | - |
dc.date.copyright | 2018-08-15 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-08 | |
dc.identifier.citation | Alzheimer's, A. (2017). 2017 Alzheimer's disease facts and figures. Alzheimer's & Dementia 13, 325-373.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7508 | - |
dc.description.abstract | 位於大腦額葉皮層及海馬迴中的β類澱粉斑塊是阿茲海默氏症患者的典型病理特徵之一,而β類澱粉蛋白由類澱粉前驅蛋白(APP)經β-secretase和γ-secretase先後切割產生並被釋放至細胞外。當β類澱粉蛋白異常累積並聚集形成β類澱粉斑塊,會使腦內產生發炎反應並進一步引發神經纖維糾結的產生,導致神經細胞死亡、大腦萎縮等現象,最終造成阿茲海默氏症之神經退化性疾病。為了減少β類澱粉蛋白的產生,我們期望找到能調控γ-secretase酵素活性的目標蛋白質。藉由RNA干擾法篩選出三種對γ-secretase作用於amyloidogenic反應路徑相較Notch路徑有選擇性影響的γ-secretase結合蛋白,並針對與阿茲海默氏症之相關性尚未被探討過的ATP6V0d1蛋白做進一步的研究。藉由慢病毒將對ATP6V0d1有抑制作用的shRNA送入共同過量表現APP-C99和胞外片段剔除之Notch蛋白(NΔE)的細胞株中,希望能確認ATP6V0d1蛋白確實具有調控γ-secretase的功能,且會選擇性地影響γ-secretase對amyloidogenic反應路徑的作用。當ATP6V0d1基因表現被削弱後,細胞內部的APP-C99及其γ-secretase切割產物─類澱粉前驅蛋白胞內片段(AICD)和NΔE及其γ-secretase切割產物─Notch蛋白胞內片段(NICD)都會同時大量累積,且APP-C99及AICD的累積倍數明顯多於NΔE及NICD增加的趨勢,顯示ATP6V0d1的抑制對γ-secretase進行amyloidogenic反應路徑有較大影響。ATP6V0d1是囊泡型ATPase的次單元之一,且已知囊泡型ATPase會協助溶酶體建立內部酸性環境,故推測抑制ATP6V0d1的表現可能會影響溶酶體內部酸鹼值,並間接影響細胞自噬作用的進行。在我們實驗中也發現,在ATP6V0d1表現量下降時,自噬作用受體蛋白p62的量和自噬作用標記蛋白LC3-II/I的比率皆有明顯的提升,顯示細胞自噬囊泡與溶酶體融合後,可能因酸鹼值改變而無法正常將蛋白質降解。這些研究結果證實,在抑制ATP6V0d1基因表現後,可能會藉由阻斷細胞自噬作用的進行,而顯著影響γ-secretase對amyloidogenic反應路徑的催化效率。這也顯示ATP6V0d1的存在對於細胞正常生理功能十分重要,且若此蛋白發生異常可能有潛在強化amyloidogenic反應路徑的風險。 | zh_TW |
dc.description.abstract | The deposition of beta-amyloid plaques in cortex and hippocampus is one of the classical pathological features of Alzheimer’s disease (AD). Amyloid precursor protein (APP) is cleaved by β-secretase and γ-secretase to produce amyloid-β (Aβ). Our RNA interference (RNAi) screening has led us to identify ATP6V0d1 as a potential γ-secretase modulator. ATP6V0d1 is a member of the γ-secretase interactome that consists of 57 distinct presenilin-1 (PS1)-binding proteins. We have demonstrated that down-regulation of ATP6V0d1 by RNAi could induce a significant reduction in γ-secretase activity. Using a HEK293-derived cell line (CCNY) that stably co-expresses yellow fluorescent protein (YFP)-tagged extracellular domain truncated Notch (NΔE) and cyan fluorescent protein (CFP)-tagged APP-C99, we found that the levels of APP-C99, APP intracellular domain (AICD), NΔE, and Notch intracellular domain (NICD) are significantly accumulated in response to downregulation of ATP6V0d1. Given that ATP6V0d1 is an integral component of the vacuolar H+-ATPase governing the maturation of autolysosomes, we examined the levels of p62 and LC3-I/II in CCNY cells that are subject to ATP6V0d1 knockdown. Our data showed that ATP6V0d1 knockdown effectively induces concomitant increases in the level of p62 and the ratio of LC3-II/LC3-I, suggesting that ATP6V0d1 knockdown could block the autophagic flux to induce concomitant accumulation of APP-C99 and NΔE. Together, the present findings suggest that ATP6V0d1 could modulate the clearance of APP-C99 through controlling the maturation of autolysosome. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:45:12Z (GMT). No. of bitstreams: 1 ntu-107-R04b21021-1.pdf: 2490049 bytes, checksum: 728029facee69bfa4c6dab1b069a4b6d (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 誌謝............................. I
中文摘要......................... II 英文摘要......................... IV 前言與研究背景.................... 1 研究動機及目標.................... 7 研究材料......................... 8 研究方法......................... 12 研究結果......................... 18 討論............................. 27 結論..............................30 參考文獻..........................31 結果圖片..........................41 | |
dc.language.iso | zh-TW | |
dc.title | 囊泡型ATPase次單元V0d1調節細胞自噬作用對類澱粉前驅蛋白恆定之影響 | zh_TW |
dc.title | The Role of Vacuolar ATPase Subunit V0d1 in Modulating Autophagic Clearance of Amyloid Precursor Protein C-terminal Fragments in Alzheimer’s Disease | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃偉邦,易玲輝 | |
dc.subject.keyword | 阿茲海默氏症,β類澱粉蛋白,ATP6V0d1,細胞自噬作用,自噬作用受體蛋白p62,自噬作用標記蛋白LC3,溶?體酸鹼值, | zh_TW |
dc.subject.keyword | Alzheimer’s disease,Amyloid-β,ATP6V0d1,Autophagy,LC3,p62,Lysosomal pH value, | en |
dc.relation.page | 52 | |
dc.identifier.doi | 10.6342/NTU201802746 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2018-08-08 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生命科學系 | zh_TW |
dc.date.embargo-lift | 2023-08-15 | - |
顯示於系所單位: | 生命科學系 |
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