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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳振中 | |
| dc.contributor.author | Yen-Ling Lin | en |
| dc.contributor.author | 林彥伶 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:42:58Z | - |
| dc.date.available | 2021-08-07 | |
| dc.date.copyright | 2018-08-07 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-03 | |
| dc.identifier.citation | (1) Welcome to CDC stacks | Deaths : leading causes for 2015 - 50010 | Stephen B. Thacker CDC Library collection https://stacks.cdc.gov/view/cdc/50010 (accessed May 29, 2018).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70899 | - |
| dc.description.abstract | 乙型類澱粉樣蛋白 (beta amyloid peptides, Aβ) 為阿茲海默症中關鍵因素，近年來研究指出寡聚物 (oligomers) 比纖維狀態具有更高細胞毒性。在本研究中，我們將Aβ培養於2,2,4-三甲基戊烷 (isooctane) 與Aerosol-OT (sodium bis(2-ethylhexyl) sulfosuccinate, AOT) 製備的逆相微胞 (reverse micelle) 中。動態光散射粒徑分析儀 (dynamic light scattering) 顯示其水合直徑約為33 nm。於25 °C培養六天後，反向萃取Aβ胜肽 (RMAβ6d) 以穿透式電子顯微鏡 (transmission electron microscope) 與OMAB抗體辨認，其為寡聚物狀態；以粒徑篩層析儀 (size exclusion chromatography) 分析其最大為54 kDa；Thioflavin-T (ThT) 數據指出具有β-sheet之反向萃取寡聚物快速生長為原纖維。固態核磁共振 (solid-state nuclear magnetic resonance) 結果顯示這些原纖維為單一構型 (monomorphism)。大部分in vitro培養之Aβ纖維具多態性 (polymorphism)，我們推斷主要源自多重成核途徑；在本實驗中，因逆相微胞之物理性限制空間，Aβ聚集由一級成核 (primary
nucleation) 主導，因此能培養出結構均一之原纖維聚集物。此發現能解釋不同阿茲海默症患者腦中，有著不同構型之核種，卻由單一聚集生長機制主導，因此產生不同結構之Aβ纖維，但卻保有單一構型。 | zh_TW |
| dc.description.abstract | Beta-amyloid peptides (Aβ) are widely considered as the key factor in the molecular pathology of Alzheimer's disease (AD). According to recent research, Aβ oligomers are considered to be a more relevant therapeutic target than other species such as the fibrillar aggregates. In this study, we were able to incubate Aβ peptides in the reverse micelles (RMs) formed by water, sodium bis(2-ethylhexyl) sulfosuccinate (AOT), and isooctane, where the molar ratio of water to AOT was adjusted to 70. The hydrodynamic diameter of the reverse micelles was found to be ca. 33 nm by dynamic light scattering (DLS). After incubated at 25 °C for 6 days, Aβ peptides were in oligomeric state as confirmed with TEM images and OMAB dot blot assay. The size of the oligomers was estimated with analytical size exclusion chromatography (SEC) to be <54 kDa. The results of Thioflavin-T (ThT) assay revealed that the extracted Aβ oligomers in Tris buffer grew rapidly into protofibrils without lag time. Surprisingly, the solid-state NMR data indicate that the molecular structure of the protofibrils is highly monomorphic. We infer that the phenomenon of structural polymorphism commonly observed in amyloid fibrils prepared in vitro is largely due to the nucleation process of the amyloidogenic peptides, where both the primary and secondary nucleation processes are occurring. In this work, when the nucleation process was dominated by a single molecular process, i.e., primary nucleation within RMs, the molecular structure of the fibrillar aggregates became monomorphic. This finding sheds considerable insight into the intriguing observation that brain tissues of individual AD patients exhibit a single predominant but distinctive Aβ fibrillar structure. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:42:58Z (GMT). No. of bitstreams: 1 ntu-107-R05223138-1.pdf: 13461107 bytes, checksum: 3523a4e658d16d2f39317fc42620748d (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 論文口試委員審定書 i
謝誌 ii 中文摘要 v 英文摘要 vi 縮寫表 vii 1.1. Aβ 胜肽與阿茲海默症之關聯性 1 1.1.1. 類澱粉蛋白 1 1.1.2. 阿茲海默症 2 1.1.3. Aβ 成核纖維化與多樣性 6 1.2. Aβ 胜肽寡聚物 7 1.2.1. 寡聚物致病機制推論 7 1.2.2. 寡聚物種類 8 1.2.3. 寡聚物之培養 11 1.3. 逆相微胞簡介 15 1.4. 研究動機 19 2.1. 化學試劑與使用儀器 20 2.1.1. 化學試劑 20 2.1.2. 使用儀器 22 2.2. 胜肽製備 23 2.2.1. 蛋白表達 23 2.2.2. 胜肽純化 26 2.2.3. 胜肽鑑定 28 2.3. 逆相微胞包覆 Aβ1-40 之製備 30 2.3.1. Aβ1-40 單體製備 30 2.3.2. 逆相微胞包覆 Aβ1-40 之製備 30 2.3.3. 反向萃取 Aβ 31 2.4. 鑑定方法 32 2.4.1. 動態光散射粒徑分析儀 32 2.4.2. 斑點印跡法 33 2.4.3. 硫黃素螢光偵測 34 2.4.4. 圓偏光二色光譜 35 2.4.5. 穿透式電子顯微鏡 36 2.4.6. 粒徑篩層析儀 37 2.4.7. 固態核磁共振儀 37 3.1. 蛋白表達製備胜肽以及其純化與鑑定 41 3.1.1. 蛋白表達 41 3.1.2. 胜肽之純化 41 3.1.3. 胜肽之鑑定 44 3.1.4. 蛋白表達之結果討論 45 3.2. 以逆相微胞包覆 Aβ1-40 單體 46 3.2.1. RMAβ1-40 之穩定度 46 3.2.2. 監測 Aβ1-40 於逆相微胞中之聚合 47 3.2.3. RMAβ 結果討論 49 3.3. 反向萃取 RMAβ 之鑑定 50 3.3.1. 寡聚物之鑑定 50 3.3.2. 原纖維之鑑定 58 3.3.3. 纖維之鑑定 63 3.3.4. 反向萃取 RMAβ 之結果討論 65 4.1. 論文總結 67 4.2. 未來展望 68 參考文獻 69 附錄 A Aβ1-42 之定點突變 82 附錄 B Aβ1-42 之基因序列設計與表達 84 附錄 C 逆相微胞平均包覆 Aβ 單體數 91 附錄 D MTBE 對於反向萃取 RMAβ 之影響 92 附錄 E Aβ 於 25 °C 培養之 ThT 監測圖 94 附錄 F 粒徑層析管柱 YMC Diol-300 之檢量線 95 附錄 G 逆相微胞之對照組 96 附錄 H 分析級超高速離心_RMAβ6d 97 附錄 I 估計反向萃取 RMAβ 中 Aβ 與 AOT 之比例 101 附錄 J 靜置培養之 Aβ1-40 纖維固態核磁共振光譜圖 102 附錄 K 估計 140 kHz 固態核磁共振實驗使用 0.5 mm 轉子中 Aβ 胜肽量 103 附錄 L 估計反向萃取 RMAβ 經除鹽後 Aβ 與 AOT 之比例 104 | |
| dc.language.iso | zh-TW | |
| dc.subject | 寡聚物 | zh_TW |
| dc.subject | 乙型類澱粉樣胜? | zh_TW |
| dc.subject | beta amyloid | en |
| dc.subject | oligomers | en |
| dc.title | 以逆相微胞製備乙型類澱粉樣多肽聚合物之研究 | zh_TW |
| dc.title | Aggregation of beta-amyloid peptides confined in reverse micelles | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 戴桓青,黃人則 | |
| dc.subject.keyword | 乙型類澱粉樣胜?,寡聚物, | zh_TW |
| dc.subject.keyword | beta amyloid,oligomers, | en |
| dc.relation.page | 105 | |
| dc.identifier.doi | 10.6342/NTU201802171 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-06 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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