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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳佩燁(Pei-Yeh Chen) | |
| dc.contributor.author | Chih-Yun Lin | en |
| dc.contributor.author | 林芝韻 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:52:00Z | - |
| dc.date.available | 2015-08-03 | |
| dc.date.copyright | 2010-08-03 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-02 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46037 | - |
| dc.description.abstract | 在先前的研究中，我們發現將貝他類澱粉蛋白(Aβ40)的第24個胺基酸由D-form Proline 取代原本的Valine合成出一條名為V24P的胜肽，當濃度高達60 μM，只有類澱粉樣的貝他類澱粉蛋白聚集沉澱，而無纖維絲的產生。有趣的是，當把V24P和貝他類澱粉蛋白(Aβ40)以同樣的濃度相混並和細胞一起培養時，可減低由貝他類澱粉蛋白(Aβ40)引起的細胞毒性。本實驗的目的是要設計並合成一系列的V24P衍生物，且探討它們對貝他類澱粉蛋白(Aβ40)所產生細胞毒性的抑制效果。首先，我們移除V24P N 端較親水性的部分，生成一段含31個胺基酸的胜肽，命名為V24P(10-40)；另外則去掉V24P C 端較疏水性的部分生成另一段名為V24P(1-28)，含28個胺基酸的胜肽。由實驗證明，V24P(10-40)在濃度30 μM 時就可以形成類似於V24P 的類澱粉樣的貝他類澱粉蛋白聚集沉積。而其降低Aβ40毒性的效果也較V24P來的顯著。因此，另外合成三個以V24P(10-40)為基礎而長度更
短的胜肽V24P(13-36)、V24P(16-33)、V24P(19-30)。然而由結果發現，這三個較短的胜肽在降低Aβ40所產生的細胞毒性方面並沒有顯著的影響，顯示了在DPro-Gly兩邊保留完整的殊水性片段是很重要的。根據以上的實驗結果，我們選擇了V24P(10-40)做為最適合的抑制劑。為了避免V24P(10-40)受體內的蛋白酶等酵素降解，我們也利用D-form 的胺基酸合成另兩條胜肽。一條和V24P(10-40)胺基酸序列完全相同的名為d-V24P(10-40)；另一條除了DPro-Gly 外，其他胺基酸序列則和V24P(10-40)完全相反，命名為d-V24P(40-10)。這兩條胜肽不但和V24P(10-40)有同樣的抑制活性，更可以抵抗腦啡肽酶(neprilysin)這類在大腦裡主要降解貝他類澱粉蛋白(Aβ40)的酵素的分解。在未來的實驗，我們會將V24P(10-40)、d-V24P(10-40)和d-V24P(40-10)做為一類胜肽型的抑制劑來進行一系列有關阿茲海默症的治療的研究。 | zh_TW |
| dc.description.abstract | Recently we have reported an Aβ40 mutant peptide V24P, which has a Val-24→DPro substitution, can form a non-fibril amyloid-like β-aggregate at a high peptide concentration (60 μM). Interestingly, the cytotoxicity of Aβ40 can be decreased when Aβ40 is co-incubated with equal molar of V24P. In this study, a series of V24P derivatives were designed and synthesized. First, we removed the N-terminal hydrophilic part of V24P to produce a peptide named V24P(10-40) and removed the C-terminal hydrophobic part of V24P to produce another peptide named V24P(1-28). A similar amyloid-like β-aggregate was formed in 30 μM V24P(10-40). This peptide has a greater effect on decreasing Aβ40 toxicity than V24P. Another three shorter peptides V24P(13-36), V24P(16-33), V24P(19-30) were synthesized. They don’t have significant effect on decreasing Aβ40 toxicity, suggesting that the integrity of the hydrophobic segments on both sides of DPro-Gly turn is important. Based on our results, V24P(10-40) was singled out as the best candidate of peptide inhibitor. To avoid degradation by proteases and peptidases in body, we used D-form amino acids to synthesize another two peptides. One of them that has the same sequence of V24P(10-40) was encoded as d-V24P(10-40) and another one with the reversed sequence except the DPro-Gly segment was encoded as d-V24P(40-10). These two peptides had an inhibitory activity similar to that of V24P(10-40) and were resistant to the digestion of neprilysin which was thought as the key Aβ-degrading enzyme in brain. The effect of these peptides as peptide inhibitors in Alzheimer’s therapy will be examined in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:52:00Z (GMT). No. of bitstreams: 1 ntu-99-R97b46034-1.pdf: 2806445 bytes, checksum: b9cead135f02772e5f33af9502fc62eb (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | Abbreviations i
Abstract iv 中文摘要 v Chapter 1 Introduction 1 1.1 Introduction of Alzheimer Disease 1 1.2 The amyloid cascade hypothesis 3 1.3 The generation and clearance of Aβ 5 1.4 The structure of Aβoligomer, fibrils, and the mechanism of fibrillogenesis 7 1.5 Strategies of treatment Alzheimer’s disease 12 1.6 The aim of this project 19 Chapter 2 Materials and Methods 20 2.1 Materials 20 2.1.1 Water 20 2.1.2 Chemical 20 2.1.3 Laboratory Instruments 23 (1) Biological safety cabinet 23 (2) Centrifuge 23 (3) Circular dichroism spectroscopy (CD) 23 (4) ELISA reader 23 (5) Fluorescence Spectrophotometer 23 (6) High performance liquid chromatography (HPLC) 23 (7) Mass spectroscopy 24 (8) Peptide synthesizer 24 (9) Ultraviolet spectroscopy 24 2.2 Methods 25 2.2.1 Peptide synthesis, purification and identification 25 (1) Solid phase peptide synthesis 25 (2) Peptide purification and identification 27 2.2.2 Determine the quantities of peptides by amino acid analysis 28 2.2.3 The secondary structure of the series of V24P derivates monitored by Circular Dichrosim (CD) spectroscopy 32 2.2.4 Amyloid fibril formation monitored by Thioflavin T (ThT) fluoromeric assay 33 2.2.5 Transmission Electron Microscopy (TEM) 34 2.2.6 Measurement of cell viability by MTT assay 35 2.2.7 Protease-resistance assay 38 Chapter 3 Results and Discussion 39 3.1 Designed of a potent inhibitor of Aβ polymerization 39 3.2 The C-terminal hydrophobic part is essential for formation of the“ amyloid-like β-aggregate” 40 3.2.1 TEM images of the V24P(10-40) and V24P(1-28) 46 3.2.2 V24P(10-40) has a greater influence on the fibrillogenesis of Aβ 47 3.3 A potent inhibitor was selected by screening the inhibitory activity 49 3.3.1 The V24P(10-40) showed the highest ability to inhibit the Aβ40-induced neurotoxicity 50 3.3.2 Concentration-dependent structural conversion of V24P(13-36), V24P(16-33) and V24P(19-30) 52 3.3.3 TEM images of high concentrated V24P(13-36), V24P(16-33) and V24P(19-30) 56 3.4 Designed D-form peptides were more resistant to endopeptidase degradation 58 3.4.1 The spectroscopic properties of d-V24P(10-40) and d-V24P(40-10) 63 3.4.2 The morphology of the D-form V24P derivatives with TEM 65 3.5 The effect of d-V24P(10-40) and d-V24P(40-10) on affecting the structural conversion of Aβ40 66 3.5.1 CD spectroscopy and ThT binding assay 66 3.5.2 TEM images 71 3.6 Measure the cytotoxicity of Aβ42 by a mouse N2a neuroblastoma system 73 Chapter 4 Conclusions and future work 74 References 77 | |
| dc.language.iso | en | |
| dc.subject | 細胞毒性 | zh_TW |
| dc.subject | 貝他類澱粉蛋白 | zh_TW |
| dc.subject | 阿茲海默症 | zh_TW |
| dc.subject | 抑制劑 | zh_TW |
| dc.subject | cytotoxicity | en |
| dc.subject | Amyloid-beta protein | en |
| dc.subject | Alzheimer’s disease | en |
| dc.subject | inhibitor | en |
| dc.title | 用於治療阿茲海默症的自殺性胜肽抑制劑之設計 | zh_TW |
| dc.title | Design of a Suicide Peptide Inhibitor for Alzheimer's Therapy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王勝仕,杜邦憲,廖永豐 | |
| dc.subject.keyword | 阿茲海默症,貝他類澱粉蛋白,細胞毒性,抑制劑, | zh_TW |
| dc.subject.keyword | Alzheimer’s disease,Amyloid-beta protein,cytotoxicity,inhibitor, | en |
| dc.relation.page | 88 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-08-02 | |
| 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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