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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳振中 | zh_TW |
dc.contributor.advisor | Chun-Chung Chan | en |
dc.contributor.author | 許詠翔 | zh_TW |
dc.contributor.author | Yung-Hsiang Hsu | en |
dc.date.accessioned | 2023-09-15T16:15:21Z | - |
dc.date.available | 2023-09-16 | - |
dc.date.copyright | 2023-09-15 | - |
dc.date.issued | 2022 | - |
dc.date.submitted | 2002-01-01 | - |
dc.identifier.citation | 1. Hippius, H., and Neundörfer, G. (2003). The discovery of Alzheimer's disease. Dialogues Clin. Neurosci. 5, 101-108.10.31887/dcns.2003.5.1/hhippius.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89686 | - |
dc.description.abstract | 阿茲海默症目前仍是一種無法治療的神經退化性疾病,由過度磷酸化之Tau蛋白所形成的神經纖維糾結是其病理特徵之一。近年來有越來越多證據指出,僅神經纖維糾結的形成就足以導致神經退化。纖維形成之前的中間態寡聚體具有更強的細胞毒性,且Tau寡聚體可能在神經元之間傳遞並誘導相鄰細胞中的Tau蛋白錯誤折疊,這對於阿茲海默症的形成具有關鍵性的病理意義,而本研究的最終目標是開發抑制寡聚體形成或促進清除寡聚體的藥物。目前對於Tau寡聚體的定義與大小仍不明確,以及寡聚體的不穩定性,使其難以研究。儘管過去研究中已經有不同方法來製備Tau寡聚體,但要製備與阿茲海默症患者構型相似的重組Tau寡聚體仍然是一個巨大的挑戰。現在用於探測Tau寡聚體構型的唯一可用工具是構型專一性抗體。在本研究中,我們從大腸桿菌表達系統製備出非常高純度的tau蛋白(2N4R,441 aa),並以肝素誘導Tau蛋白錯誤折疊,而肝素是一種已知能觸發Tau蛋白聚集的聚陰離子。我們優化了誘導條件,以最大化寡聚體的產率,透過粒徑篩析層析法(SEC)測定,並獲得了一段連續分佈的寡聚體,範圍從300 KDa到3 MDa(7-mer到70-mer),具有和阿茲海默症患者腦中寡聚體相似的構型抗原決定位,能被構型專一性Tau抗體Alz-50、TOMA和T22辨認。在粒徑篩析層析光譜圖中,Tau寡聚體波峰位置對應於斯托克斯半徑(Rs)18.0 nm,此Tau寡聚體在分析級超高速離心下,沉降曲線在24.5S左右達到峰值。且透過穿透式電子顯微鏡觀察到Tau寡聚體為顆粒狀聚集體,而不是棒狀原纖維。根據Siegel-Monte公式分析,我們製備佔比最多的寡聚體分子量為1.85 MDa(~40 mer),類似於從阿茲海默症患者腦中分離出的Tau寡聚體的大小。透過開發這些方法,我們以合理的產率獲得了毫克級約20-40個蛋白質分子組成的顆粒狀Tau寡聚體。它們具有類似於阿茲海默症患者大腦中發現的Tau寡聚體的構型抗原決定位,這有助於未來針對tau寡聚體的藥物開發。 | zh_TW |
dc.description.abstract | Alzheimer's disease (AD) is still an untreatable neurodegenerative disease. Neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein is one of its key pathological features. In recent years, increasing evidence has shown that the formation of neurofibrillary tangles alone is sufficient to cause neurodegeneration. The oligomeric intermediates that precede fibril formation have stronger cytotoxicity, and tau oligomers may transmit between neurons and induce tau misfolding in neighboring cells, a key pathological process in the progression of AD. The ultimate goal of this study is to develop drugs that can inhibit oligomer formation or promote oligomer clearance. At present, the definition of tau oligomers and their size range remain unclear. The instability of tau oligomers makes them difficult to study. Although different methods for preparing tau oligomers have been previously reported, it remains a great challenge to prepare recombinant tau oligomers with similar conformations as those found in AD patients. Currently, the only available tools to probe tau oligomer conformations are conformation-specific antibodies. In this study, we started with very high purity tau proteins (2N4R, 441 aa) prepared from E. coli expression system. Tau misfolding was induced by heparin, a polyanion known to trigger tau aggregation. We optimized the induction condition to maximize the yield of oligomeric species, as determined by size-exclusion chromatography (SEC). We obtained a continuum of oligomeric species that range from 300 KDa to 3 MDa (7-mer to 70-mer), and they share conformational epitopes found on oligomers from AD patient brains, recognized by conformational tau antibodies Alz-50, TOMA, and T22. The tau oligomer peak position in the SEC chromatogram corresponded to the Stokes radius (Rs) of 18.0 nm. When this peak fraction was submitted to analytical ultracentrifugation, the sedimentation profile peaked around 24.5S. Under transmission electron microscopy, they appeared as granular aggregates rather than rod-like protofibrils. According to Siegel-Monte analysis, the most abundant species in our preparation has a molecular weight of 1.85 MDa (~40-mer), similar to the size of tau oligomers isolated from AD patient brains. By developing these protocols, we obtained granular tau oligomers with around 20-40 protein units at milligram scale with a reasonable yield. They carry conformational epitopes similar to tau oligomers found in AD patient brains, which is useful for future drug development targeting tau oligomers. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-15T16:15:21Z No. of bitstreams: 0 | en |
dc.description.provenance | Made available in DSpace on 2023-09-15T16:15:21Z (GMT). No. of bitstreams: 0 | en |
dc.description.tableofcontents | 口試委員會審定書 I
中文摘要 II Abstract IV 圖目錄 IX 表目錄 XI 縮寫表 XII 第一章 緒論 1 1.1阿茲海默症 1 1.1.1阿茲海默症介紹 1 1.1.2類澱粉蛋白假說 2 1.1.3Tau蛋白假說 4 1.2Tau寡聚體 5 1.2.1Tau寡聚體的重要性 5 1.2.2Tau蛋白的誘導方法 6 1.2.3Tau寡聚體大小 8 1.2.4Tau寡聚體的毒性 8 1.3Tau寡聚體的純化 9 1.3.1蔗糖梯度離心法 9 1.3.2粒徑排阻層析法 11 1.4Tau寡聚體的分析 11 1.4.1Tau寡聚體的尺寸及形貌 11 1.4.2Tau寡聚體鑑定 12 1.5研究動機 13 第二章 實驗材料與方法 14 2.1實驗材料與實驗儀器 14 2.1.1化學藥品與試劑 14 2.1.2耗材與套組 15 2.1.3一級抗體 15 2.1.4二級抗體 16 2.1.5實驗儀器 16 2.2Tau蛋白的製備 17 2.3Tau蛋白的誘導條件 18 2.4硫黃素螢光偵測 18 2.5粒徑篩析層析法 19 2.5.1製備級SEC管柱(HiPrep 16/60 Sephacryl S-500 HR) 20 2.5.2分析級SEC管柱(Agilent Bio SEC-5) 21 2.6斑點印跡法 22 2.7動態光散射粒徑分析儀 24 2.8穿透式電子顯微鏡 25 2.9分析級超高速離心 26 2.10Siegel-Monte分析法 28 第三章 研究結果與討論 29 3.1誘導Tau蛋白方法與鑑定 29 3.1.1以肝素誘導Tau蛋白聚集 29 3.2使用製備級SEC純化Tau聚集物 34 3.2.1製備級SEC 34 3.2.2斑點印跡法鑑定 36 3.2.3以動態光散射粒徑分析儀分析Tau聚集體 37 3.3利用分析級SEC純化Tau聚集物 38 3.3.1分析級SEC 38 3.3.2斑點印跡法鑑定 40 3.4以分析級SEC分析寡聚體大小 42 3.5Tau寡聚體之TEM鑑定 43 3.6以分析級超高速離心分析Tau寡聚體 45 3.7以Siegel-Monte分析法分析Tau寡聚體 46 第四章 結論與未來展望 48 4.1論文總結 48 4.2未來展望 49 參考文獻 50 附錄 57 附錄A 以製備級SEC管柱分離蛋白質標準品 57 附錄B 以分析級SEC管柱分離標準品 59 | - |
dc.language.iso | zh_TW | - |
dc.title | Tau蛋白寡聚體的製備與特性研究 | zh_TW |
dc.title | Preparation and characterization of Tau protein oligomers | en |
dc.type | Thesis | - |
dc.date.schoolyear | 110-2 | - |
dc.description.degree | 碩士 | - |
dc.contributor.oralexamcommittee | 陳佩燁 | zh_TW |
dc.contributor.oralexamcommittee | Hwan-Ching Tai;Pei-Yeh Chen | en |
dc.subject.keyword | Tau寡聚體,肝素,粒徑篩析層析法,構形辨識抗體,分析級超高速離心,穿透式電子顯微鏡, | zh_TW |
dc.subject.keyword | Tau oligomer,heparin,size-exclusion chromatography,conformational antibody,analytical ultracentrifugation,transmission electron microscopy, | en |
dc.relation.page | 60 | - |
dc.identifier.doi | 10.6342/NTU202203914 | - |
dc.rights.note | 同意授權(全球公開) | - |
dc.date.accepted | 2022-09-27 | - |
dc.contributor.author-college | 理學院 | - |
dc.contributor.author-dept | 化學系 | - |
顯示於系所單位: | 化學系 |
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