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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49648完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 戴桓青(Hwan-Ching Tai) | |
| dc.contributor.author | Hao-Tai Lin | en |
| dc.contributor.author | 林豪泰 | zh_TW |
| dc.date.accessioned | 2021-06-15T11:39:44Z | - |
| dc.date.available | 2021-08-24 | |
| dc.date.copyright | 2016-08-24 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-15 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49648 | - |
| dc.description.abstract | Aβ胜肽堆積形成的斑塊以及tau蛋白堆積形成的神經纖維糾結為阿茲海默症中最主要的病理特徵。然而Aβ胜肽病變和tau蛋白病變之間的關聯性是最為關鍵但尚未能解決的議題。在先前的研究中，我們在患有阿茲海默症的大腦的神經突觸中觀察到過磷酸化且錯誤折疊的tau蛋白沉積物。於此研究中，我們使用有大量斑塊而沒有神經纖維糾結的APP/PS1老鼠模型以及定量磷酸化蛋白質體學來探討tau的過磷酸化。我們在控制組和APP/PS1老鼠的突觸體中發現到12個tau蛋白的磷酸化位置。然而，其中有6個磷酸化位置 (S199, S202, S396, S400, S404, S416) 在APP/PS1的老鼠中可以發現到磷酸化增加的量在統計上有顯著的差異。tau蛋白過磷酸化圖譜表明，Aβ會活化在突觸體中的脯氨酸導引蛋白質激酶 (proline-directed kinase, PDK)。
我們透過全面性的磷酸化蛋白質體學分析，發現到包含tau蛋白在內，有40個突觸體蛋白被過磷酸化，而這些蛋白又尤其是被PDK及酸導引蛋白質激酶 (acid-directed kinase, ADK) 給磷酸化。藉由更進一步的序列分析，我們發現到cyclin-dependent kinase 5 (CDK5) 以及 casein kinase 2 (CK2) 分別為被活化的PDK及ADK。我們的數據表明，CDK5 在Aβ胜肽病變和tau蛋白病變之間扮演重要的連結，且阻斷CDK5 的活化將可能是在阿茲海默症中具有潛力的治療方式。 | zh_TW |
| dc.description.abstract | The key pathological features of Alzheimer’s disease (AD) are aggregates of Aβ peptide (plaques) and tau protein (tangles). The relation between Aβ pathology and tau pathology is a critical but unresolved issue. We previously observed that neuronal synapses in AD-affected brains showed deposits of hyperphosphorylated and misfolded tau protein. Here we investigated the cause of tau hyperphosphorylation in synapses using APP/PS1 mice and quantitative phosphoproteomics. We found 12 tau phosphosites in mouse synaptosomes, which were identical for APP/PS1 and control mice. Importantly, 6 of these sites (S199, S202, S396, S400, S404, S416) showed statistically significant increase in APP/PS1 mice. The pattern of tau hyperphosphorylation suggested the activation of proline-directed kinases (PDK) by Aβ at synapses.
Through global phosphoproteomic analysis, we found 40 synaptic proteins including tau which were hyperphosphorylated, especially by proline-directed kinases and acid-directed kinases. Further motif analysis suggested cyclin-dependent kinase 5 (CDK5) as the highly activated proline-directed kinase, and casein kinase II (CK2) as the highly activated acid-directed kinase. Our data suggests that CDK5 is an important link between Aβ and tau pathology, and that blocking the activation of CDK5 may be a potential therapeutic strategy for AD. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T11:39:44Z (GMT). No. of bitstreams: 1 ntu-105-R03223207-1.pdf: 7037155 bytes, checksum: cab0a70402c30c252c210b94bb51a7a6 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 口試委員會審定書 #
誌謝 i 中文摘要 ii ABSTRACT iii Table of Contents iv LIST OF FIGURES vi LIST OF TABLES viii Abbreviations ix Chapter 1 Introduction 1 1.1 Cell types in the brain 1 1.2 Alzheimer disease and synaptic dysfunction 3 1.3 Phosphorylation pattern of tau protein 4 1.4 Tau protein kinases 10 1.5 Mass spectrometry for phosphoproteomics 13 1.6 Label-free quantification in mass spectrometry 17 1.7 Aim of this study 20 Chapter 2 Results and Discussion 21 2.1 Phosphorylation sites, label-free quantification of phosphopeptides, and kinases of tau 21 2.2 Label-free quantification of non-tau phosphopeptides 33 2.3 Identification of kinases involved in tau hyperphosphorylation 38 2.4 Reported CDK5 substrates 43 2.5 Functional analysis and interaction of hyperphosphorylated proteins in synaptosomes of APP/PS1 mouse 46 Chapter 3 Conclusion 50 Chapter 4 Materials and Methods 52 4.1 Materials 52 4.1.1 Mice for synaptosome preparation 52 4.1.2 Chemicals 52 4.2 Synaptosome preparation 53 4.3 LC-MS/MS analysis 54 4.3.1 LC-MS/MS analysis 54 4.3.2 Database Search 54 4.3.3 Quantitative analysis by IDEAL-Q 55 4.4 Bioinformatic analysis 56 4.4.1 Functional analysis by ClueGO 56 4.4.2 Phosphorylation site motif 56 4.4.3 Protein-Protein interaction network 56 4.5 Western blot 57 4.5.1 SDS-PAGE using home-made gradient gel 57 4.5.2 Western transfer and blotting 57 REFERENCE 59 APPENDIX 77 | |
| dc.language.iso | en | |
| dc.title | 以定量磷酸化蛋白質體學分析阿茲海默症小鼠模型中神經突觸體的病理變化 | zh_TW |
| dc.title | Quantitative phospho-proteomic analysis of pathological changes at neuronal synapses in a mouse model of Alzheimer disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王宗興(Tsung-Shing Wang),韓嘉莉(Chia-Li Han) | |
| dc.subject.keyword | 阿茲海默症,斑塊,神經纖維糾結,過磷酸化, | zh_TW |
| dc.subject.keyword | Aβ,tau,APP/PS1,plaque,tangle, | en |
| dc.relation.page | 82 | |
| dc.identifier.doi | 10.6342/NTU201602446 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-08-16 | |
| 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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