請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55097完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳振中 | |
| dc.contributor.author | Wan-Cheng Yu | en |
| dc.contributor.author | 余婉琤 | zh_TW |
| dc.date.accessioned | 2021-06-16T03:47:07Z | - |
| dc.date.available | 2020-02-25 | |
| dc.date.copyright | 2015-02-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-01-29 | |
| dc.identifier.citation | CH1
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55097 | - |
| dc.description.abstract | 錯誤摺疊的蛋白質堆積，以及在細胞質與神經細胞中的纖維纏結為阿茲海默症的主要特徵。此錯誤摺疊的蛋白主要由β-amyloid(Aβ)類澱粉樣蛋白組成，其中尤以Aβ1-40與Aβ1-42為主。過去由於在神經退化性疾病中發現大量纖維沉澱，因此長久以來認為纖維是影響阿茲海默症的主要因素。然而現今已有許多證據提出可溶性的寡聚物才是造成細胞毒性，引起細胞死亡的元兇。在腦中的許多輔助因子也漸漸受到大家的重視，在腦中濃度異常高的金屬，如Zn2+, Cu2+及Fe3+，都被發現在斑塊中與Aβ有交互作用，其中鋅離子被發現有促進聚集的形成，與穩定寡聚物形貌的能力。因此我們嘗試用鋅離子在特定條件控制下得到穩定的寡聚物，以進行結構研究，藉以了解聚集因素。
在本實驗中，我們利用濃度比例為1：1的鋅離子與Aβ1-40，在25 °C靜置條件下，培養出圓球狀，直徑平均為12−25 nm，可被A11抗體辨識的寡聚物。此Zn2+-Aβ1-40寡聚物由35−50個Aβ1-40聚集而成，其聚集速度快，二級結構之β特徵較一般Aβ1-40低，但穩定性高，形貌與β特徵均可維持1週以上。我們利用EDTA的實驗得知此寡聚物在移除了鋅離子後仍為on-pathway的中間物。此外，Zn2+對成熟纖維的堆疊也會產生影響。藉由固態核磁共振技術，我們發現Zn2+-Aβ1-40與Tycko及Ishii教授團隊得到的纖維與中間體結構均不相同。我們也從訊號的半高寬發現，本實驗中的金屬螯合寡聚物可能不具同質(homogeneous)的結構，因此導致圖譜解析度不佳。至於Zn2+-Aβ1-40的分子結構還有待進一步研究。 | zh_TW |
| dc.description.abstract | Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The senile plaques consist mainly of β-amyloid (Aβ) peptide with 40 or 42 residues, which may induce progressive neurodegeneration. It has long been reasoned that Aβ fibrils in extracellular plaques is an underlying trigger of neurodegeneration in AD. However, emerging evidences support that prefibrillar soluble oligomers may play a key role in neuronal toxicity inducing synaptic dysfunction in AD patients. Abnormally high concentration of metal ions such as Zn2+, Cu2+, and Fe3+ have been found in senile plaques and these ions would interact with Aβ. It has been found in vitro that Zn2+ ion promotes and stabilizes the oligomerization of Aβ.
In this study, we stabilize the oligomeric aggregates of 13C- and 15N-labeled Aβ1-40 by adding equivalent amounts of Zn2+ ions. The peptides form spherical aggregates with diameter of 12−25 nm as indicated by Transmission electron microscope images. Together with the circular dichroism and Thioflavin T fluorescence data we find these oligomers have the beta-strand conformation. Using analytical ultracentrifugation (AUC) and size exclution chromatography (SEC) methods, we found these oligomers were composed of by 35−50 mer of Aβ1-40. We further investigate the evolution of Zn2+ chelated Aβ1-40 oligomer by adding EDTA to remove Zn2+ ions. We found that the Aβ1-40 oligomers will fibrillize after the removal of Zn2+ ions. These Zn2+-Aβ1-40 oligomers are on-pathway oligomers. According to our solid-state NMR results, our oligomer structure are different from the results reported by Tycko on fibrils and by Ishii on intermediates. However, we also found that the poor resolution of NMR data may be due to the inhomogeneous of the structure of Zn2+-Aβ1-40 oligomers. Further investigations are needed to solve the molecular structure of the oligomers. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T03:47:07Z (GMT). No. of bitstreams: 1 ntu-104-R01223124-1.pdf: 8602173 bytes, checksum: 7c60fb39304f431c1388d8cb2be3687a (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 第一章 序論……………………………………………………………1
1-1 類澱粉樣蛋白纖維…………………………………………………………….1 1-1-1 類澱粉樣蛋白特性…………………………………………………….1 1-1-2 蛋白摺疊與類澱粉樣蛋白之形成機制……………………………….3 1-1-3 類澱粉樣纖維與多肽鏈聚集的不同樣貌…………………………….4 1-2 Aβ胜肽與阿茲海默症………………………………………………………...7 1-3 Aβ寡聚物……………………………………………………………………..10 1-3-1 寡聚物的特性………………………………………………………….10 1-3-2 Aβ寡聚物的種類……………………………………………………….12 1-4 環境中分子影響Aβ聚集與穩定……………………………………………..15 1-4-1 與Aβ作用的環境分子………………………………………………...15 1-4-2金屬離子與Aβ胜肽的交互作用………………………………………16 1-5 固態核磁共振光譜應用於Aβ結構探討……………………………………..20 1-5-1 Aβ纖維之結構探討……………………………………………………..20 1-5-2 Aβ聚集體與金屬離子螯合Aβ之結構探討…………………………...22 1-6 研究動機……………………………………………………………………….26 1-7 參考文獻……………………………………………………………………….27 第二章 合成與鑑定……………………………………………………34 2-1 材料與使用儀器………………………………………………………………..34 2-1-1 化學藥品…………………………………………………………………34 2-1-2 實驗儀器…………………………………………………………………36 2-2 胜肽製備………………………………………………………………………..38 2-2-1 蛋白表達製備Aβ1-40胜肽………………………………………………38 2-2-2 胜肽純化…………………………………………………………………43 2-2-3 胜肽鑑定…………………………………………………………………46 2-3 鋅離子螯合之Aβ1-40寡聚物製備……………………………………………...53 2-4 鋅離子螯合之Aβ1-40寡聚物鑑定…………………………………………..54 2-4-1 寡聚物形貌………………………………………………………………54 2-4-2 寡聚物特徵………………………………………………………………55 2-4-3 寡聚物二級結構…………………………………………………………58 2-4-4 寡聚物大小………………………………………………………………60 2-4-5 胜肽與鋅離子結合比例…………………………………………………64 2-5 鋅離子螯合之Aβ1-40寡聚物演化……………………………………………...65 2-5-1 加入鋅離子對成熟纖維的影響…………………………………………65 2-5-2 去除鋅離子對鋅螯合之寡聚物的影響…………………………………66 2-6 鋅離子螯合之Aβ1-40寡聚物結構鑑定………………………………………...67 2-6-1 核磁共振基本原理………………………………………………………67 2-6-2 固態核磁共振技術………………………………………………………69 2-7 參考文獻………………………………………………………………………..73 第三章 實驗結果與討論………………………………………………77 3-1 蛋白表達製備胜肽及其純化與鑑定…………………………………………..77 3-1-1 Aβ1-40蛋白表達…………………………………………………………...77 3-1-2 Aβ1-40蛋白表達之優化…………………………………………………...78 3-1-3 Aβ1-40胜肽純化與鑑定…………………………………………………...80 3-2 鋅離子螯合之Aβ1-40寡聚物之鑑定…………………………………………...88 3-2-1 鋅離子螯合寡聚物特徵…………………………………………………88 3-2-2 鋅離子螯合寡聚物二級結構……………………………………………91 3-2-3 鋅離子螯合寡聚物大小…………………………………………………93 3-2-4 胜肽與鋅離子結合比例…………………………………………………97 3-3 鋅離子螯合之Aβ1-40寡聚物之演化…………………………………………...98 3-3-1 加入鋅離子對成熟纖維的影響…………………………………………98 3-3-2 去除鋅離子對鋅螯合之寡聚物的影響………………………………..100 3-4 Aβ1-40寡聚物分子結構之鑑定-固態核磁共振光譜…………………………..104 3-5參考文獻…………………………..……………………………………………110 第四章 總結與未來展望 ……………………………………………111 4-1 論文總結……………………..………………………………………………...111 4-2 未來展望……………………………………………………………………….112 4-3 參考文獻……………………………………………………………………….112 | |
| dc.language.iso | zh-TW | |
| dc.subject | 澱粉樣蛋白 | zh_TW |
| dc.subject | 寡聚物 | zh_TW |
| dc.subject | 鋅離子 | zh_TW |
| dc.subject | Zn | en |
| dc.subject | Abeta | en |
| dc.subject | oligomer | en |
| dc.title | 以鋅離子螯合之類澱粉樣多肽分子寡聚物之結構探討 | zh_TW |
| dc.title | Structural Elucidation of Zn2+ Ions Chelated
Oligomeric Aggregates of Amyloid-Beta Peptides | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳韻如,黃人則,戴桓青 | |
| dc.subject.keyword | 澱粉樣蛋白,鋅離子,寡聚物, | zh_TW |
| dc.subject.keyword | Zn,Abeta,oligomer, | en |
| dc.relation.page | 113 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-01-30 | |
| 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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