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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳佩燁 | |
| dc.contributor.author | Ya-Han Wang | en |
| dc.contributor.author | 王雅涵 | zh_TW |
| dc.date.accessioned | 2021-06-17T05:03:41Z | - |
| dc.date.available | 2023-08-01 | |
| dc.date.copyright | 2018-08-01 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-07-23 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71300 | - |
| dc.description.abstract | 阿茲海默症是一種慢性的神經退化疾病，也是最常見的失智症型態。目前普遍認為造成阿茲海默症的最主要原因是類澱粉蛋白 β (Aβ) 在大腦的堆積。Aβ 是前類澱粉蛋白的代謝產物, 在類澱粉蛋白生成途徑中經由 β- 和 γ-secretase 的剪切而產生。在 γ-secretase 剪切後，產生的 Aβ 會被釋出的細胞外，並堆積形成寡聚體或纖維。過去有許多研究專注於探討 Aβ 纖維的形成機制，但是較少有研究關注在 γ-secretase 剪切後的 Aβ 胜肽在細胞膜上的動態行為，包含如何被釋出以及如何聚集。此外，曾有研究指出細胞膜的組成會影響膜的流動性，進而改變 Aβ 的生成和堆積。然而 Aβ 胜肽在細胞膜中的動態行為是否會受到胞膜成分的影響，目前仍是未知。
本研究主要目的為以螢光相關光譜技術建立一個可觀察 Aβ 胜肽在膜中的動態行為的方法。我們已成功地合成並純化與前類澱粉蛋白穿膜區相符的胜肽序列，並加上螢光標定，也成功地在序列中的 γ-secretase 剪切位中插入一個光敏感化合物，以利用光解的方式模仿 γ-secretase 剪切。我們也建立了一個製造胜肽鑲嵌脂質體以及胜肽鑲嵌脂雙層的方法，並且初步地測試了適合的螢光相關光譜條件。在未來，我們可進一步將此系統結合已合成的螢光標定光敏感胜肽，觀察光解後前類澱粉蛋白氨基端部分在膜中移動之動態行為，以及動態行為與細胞膜組成成分之關係。 | zh_TW |
| dc.description.abstract | Alzheimer’s disease (AD) is a slowly progressing neurodegenerative disease and the most common type of dementia. The accumulation of amyloid-β (Aβ) in brain is generally considered to be the major culprit of AD. Aβ is a catabolic product of amyloid precursor protein (APP), generated in the amyloidogenic pathway by β- and γ-secretase cleavage. After γ-secretase cleavage, Aβ peptides will be released into extracellular spaces and aggregate into oligomers and fibrils. Despite numerous researches of fibrillogenesis mechanism, there are very few studies exploring how Aβ peptides are released from membrane and associate together after the γ-secretase cleavage. In addition, it has been reported that membrane fluidity, which is affected by lipid composition, can influence Aβ generation and aggregation. Whether the dynamic behavior of Aβ peptides in the membrane is affected by lipid composition or not is rarely discussed.
In this study, we aimed to develop a method to observe the dynamic behavior of Aβ peptide in membrane with fluorescence correlation spectroscopy (FCS). We have successfully synthesized the fluorophore-labeled peptide corresponding to APP transmembrane region, as well as the one with a photolabile linker to mimic the γ-secretase cleavage on APP. We have also built a method to prepare peptide-inserted liposomes and lipid bilayers, and preliminarily set up a suitable condition for FCS measurements. This system, combined with the fluorescent photolabile linker introduced peptide we produced, can allow us to further investigate the movement of N-terminus of APP after photolysis in membrane with different lipid composition. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T05:03:41Z (GMT). No. of bitstreams: 1 ntu-107-R05b46006-1.pdf: 4494762 bytes, checksum: a9e38d2f4a63c3f44a12efffe467008f (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract ii Abbreviations iii Chapter 1 Introduction 1 1.1 Alzheimer’s disease 1 1.2 Amyloid hypothesis 3 1.3 Fibrillogenesis of Amyloid-β 5 1.4 Interaction of Aβ and membrane 6 1.5 The role of omega-3 fatty acid in Alzheimer’s disease 9 1.6 Fluorescence correlation spectroscopy and its application on molecular dynamic behavior 10 1.7 Aims and experiment design 13 Chapter 2 Materials and Methods 16 2.1 Materials 16 2.1.1 Chemical 16 2.1.2 Laboratory instruments 18 2.2 Methods 20 2.2.1 Solid-phase peptide synthesis 20 2.2.2 Peptide purification 21 2.2.3 Peptide fluorescent labeling 23 2.2.4 Liposome preparation 24 2.2.5 Circular dichroism analysis 25 2.2.6 Dynamic light scattering analysis 25 2.2.7 Fluorescence correlation spectroscopy measurements 25 Chapter 3 Results 27 3.1 Preparation of fluorescently labeled peptides 27 3.1.1 Peptide synthesis and purification of KKWK-Aβ(22-55) and KKWK-Aβ(22-Linker42-55) 27 3.1.2 The difficulties of fluorescent-labeling on peptide N-terminus 34 3.1.3 Peptide synthesis and purification of KKWK-Aβ(22-55)-E22C and KKWK-Aβ(22-Linker42-55)-E22C 36 3.1.4 The difficulties of fluorescent-labeling on cysteine of KKWK-Aβ(22-55)-E22C 41 3.1.5 The instability of peptide KKWK-Aβ(22-55)-E22C 45 3.1.6 Peptide synthesis and purification of CKKWK-Aβ(22-55) and CKKWK-Aβ(22-Linker42-55) 51 3.1.7 Fluorescent-labeling on CKKWK-Aβ(22-55) and CKKWK-Aβ(22-Linker42-55) and purification 59 3.1.8 The instability of peptide CKKWK-Aβ(22-55) 65 3.2 Liposome preparation and FCS measurements 68 3.2.1 Optimization of liposome preparation protocol with unlabeled peptide 68 3.2.2 Liposome preparation with dye-labeled peptide 74 3.2.3 FCS measurements of dye-labeled peptide in DOPC and DMPC at lower peptide to lipid molar ratio 81 3.2.4 Epifluorescence Microscopy image of dye-labeled peptide in DOPC 86 Chapter 4 Discussion 88 4.1 Dye-labeled peptide preparation 88 4.2 Liposome preparation 89 4.3 FCS measurements 90 Chapter 5 Future work 91 References 93 | |
| dc.language.iso | en | |
| dc.subject | 阿茲海默症 | zh_TW |
| dc.subject | 脂質體 | zh_TW |
| dc.subject | 前類澱粉蛋白 | zh_TW |
| dc.subject | 螢光標定 | zh_TW |
| dc.subject | 螢光相關光譜 | zh_TW |
| dc.subject | amyloid precursor protein | en |
| dc.subject | liposome | en |
| dc.subject | fluorescence correlation spectroscopy | en |
| dc.subject | fluorescent labeling | en |
| dc.subject | Alzheimer’s disease | en |
| dc.title | 以二維螢光影像及螢光相關光譜探討Aβ胜肽在膜中之動態行為 | zh_TW |
| dc.title | Exploring the Dynamic Behavior of Aβ Peptides in Membranes by 2D-Fluorescence Imaging and Fluorescence Correlation Spectroscopy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 郭青齡,廖永豐,林達顯 | |
| dc.subject.keyword | 阿茲海默症,前類澱粉蛋白,螢光標定,脂質體,螢光相關光譜, | zh_TW |
| dc.subject.keyword | Alzheimer’s disease,amyloid precursor protein,fluorescent labeling,liposome,fluorescence correlation spectroscopy, | en |
| dc.relation.page | 107 | |
| dc.identifier.doi | 10.6342/NTU201801763 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-07-24 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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