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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51514完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳佩燁(Pei-Yeh Chen) | |
| dc.contributor.author | Po-Ting Chen | en |
| dc.contributor.author | 陳柏廷 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:37:03Z | - |
| dc.date.available | 2021-02-15 | |
| dc.date.copyright | 2016-02-15 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2016-01-26 | |
| dc.identifier.citation | 1. Jellinger, K. A. (2006) Alzheimer 100--highlights in the history of Alzheimer research. J Neural Transm 113, 1603-1623
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51514 | - |
| dc.description.abstract | 腦啡肽酶(neprilysin)被視為最重要的類澱粉降解蛋白，由於它在生理上的表現量不僅隨著年齡的增長而遞減和類澱粉的堆積情況也呈現負相關，故被認為對於偶發性阿茲海默症的促成有著密切的關聯。近幾年的許多研究中都表示調控腦啡肽酶增加其表現量對於阿茲海默症的預防與治療是有希望的。本篇實驗中，我們利用先前已建立用來偵測類澱粉貝塔蛋白降解的高靈敏螢光分析平台來篩選25種薑黃素衍生物對於調控腦啡肽酶活性的能力。我們意外地發現了雙羥基薑黃素、單羥基去甲基薑黃素、單羥基去雙甲基薑黃素及雙羥基去雙甲基薑黃素這4種化合物會增加腦啡肽酶的活性而薑黃素本身卻不會。而此我們在一系列細胞以及動物實驗的數據結果中，證實了這些多羥基薑黃素衍生物調控，使腦啡肽酶活性的增加，乃是由其信使核糖核酸和蛋白質的表現量調控增加所造成。最後我們在動物中，發現餵食雙基因轉殖鼠(APPswe/PS1dE9)單羥基去甲基薑黃素能增加腦內腦啡肽酶的量，並減少大腦皮層及海馬迴內類澱粉貝塔蛋白的堆積。透過此篇實驗的結果，相信此類多羥基薑黃素衍生物在防止罹患阿茲海默症上具有預防的潛力。 | zh_TW |
| dc.description.abstract | Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer’s disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer’s disease. Here, we used a sensitive fluorescence-based Aβ digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. We surprisingly found that four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids on upregulating NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding of monohydroxylated demethoxycurcumin to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer’s disease. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:37:03Z (GMT). No. of bitstreams: 1 ntu-104-D98b46006-1.pdf: 14649407 bytes, checksum: 4bdaa149d36b07ff37b258a9b280e721 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 謝誌 i
中文摘要 iii Abstract iv Abbreviations v Contents ix Figure contents xi Table contents xiii Chapter 1 Introduction 1 1.1 Introduction of Alzheimer Disease 1 1.2 Neprilysin 8 1.3 Therapeutic strategies of combating AD 12 1.4 Previous studies of herbal extracts on combating Alzheimers 16 1.5 Turmeric active component, curcumin 18 1.6 The aim of this thesis 22 Chapter 2 Materials and Methods 25 2.1 Materials 25 2.1.1 Water 25 2.1.2 Chemicals 25 2.1.3 Screened compounds 30 2.1.4 Cell lines 35 2.1.5 Animals 35 2.2 Methods 36 2.2.1 Synthesis of the quenched fluorogenic peptide substrates 36 2.2.2 Conditions of HPLC purification 37 2.2.3 Specificity of qf-Aβ(1-7)C and qf-Aβ(12-16)AAC for various Aβ-degrading enzymes 41 2.2.4 Cell-based NEP activity assay using qf-Aβ(1-7)C as substrate 42 2.2.5 Cell-based NEP activity assay using qf-Aβ(12-16)AAC as substrate 43 2.2.6 Protease inhibition assay 43 2.2.7 Differentiation of SH-SY5Y cells 44 2.2.8 Human NEP-cDNA transfection 44 2.2.9 Determination of the optimal selection antibiotic (G418) concentration (kill curve generation) 45 2.2.10 Procedure of producing stably-transfected cell lines 48 2.2.11 Western blotting 49 2.2.12 Animal experiment 55 2.2.13 Tissue preparation 56 2.2.14 Protein extraction for Aβ ELISA analysis 56 2.2.15 Aβ40 and Aβ42 ELISAs 57 2.2.16 Real-Time PCR Analysis 58 2.2.17 The Relative Standard Curve Method for qPCR data analysis 61 2.2.18 DNA methylation analysis by bisulfite sequencing 62 Chapter 3 Results 63 Part 1. Compounds screening 63 3.1 The fluorescence-based Aβ digestion assay for NEP activity examination 63 Part 2. Cell assay 66 3.2.1 The effect of curcumin analogs on NEP activity in cells 66 3.2.2 Optimization of the experimental conditions 69 3.2.3 Compounds no.7, 8, 10, 20 upregulate NEP activity rather than other Aβ-degrading enzymes 72 3.2.4 Effect of compounds no.7 & 8 in NEP protein expression and mRNA levels 74 Part 3. Animal experiment- normal B6C3 mice (short-term treatment) 81 3.3 Effect of compound no.7 & 8 on NEP mRNA levels in the mice brain 81 Part 4. Animal experiment-APPswe/PS1dE9 transgenic mice (long-term treatment) 84 3.4.1 Effect of compound no.7 on Aβ accumulation in the mice hippocampus and cortex 84 3.4.2 Effect of compound no.7 on NEP mRNA levels in the mice hippocampus and cortex 87 3.5 Effect of compound no.7 & 8 on DNA methylation of NEP in N2a cells 89 Chapter 4 Discussion 93 Chapter 5 Conclusions and Future works 103 Appendix 105 References 106 | |
| dc.language.iso | en | |
| dc.subject | 類澱粉貝塔蛋白 | zh_TW |
| dc.subject | 去甲基薑黃素衍生物 | zh_TW |
| dc.subject | 阿茲海默症 | zh_TW |
| dc.subject | 多羥基薑黃素衍生物 | zh_TW |
| dc.subject | 腦啡?? | zh_TW |
| dc.subject | 薑黃素 | zh_TW |
| dc.subject | 類澱粉 | zh_TW |
| dc.subject | Alzheimer disease | en |
| dc.subject | demethylated curcuminoid | en |
| dc.subject | polyhydroxycurcuminoid | en |
| dc.subject | neprilysin | en |
| dc.subject | curcumin | en |
| dc.subject | amyloid | en |
| dc.subject | Aβ | en |
| dc.title | 以多羥基薑黃素衍生物提升腦啡肽酶來預防阿茲海默症 | zh_TW |
| dc.title | Toward Prevention of Alzheimer’s Disease by Using Polyhydroxycurcuminoids to Upregulate Neprilysin | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 張文章,余榮熾,郭敏豪,侯文琪,王勝仕 | |
| dc.subject.keyword | 阿茲海默症,類澱粉貝塔蛋白,類澱粉,薑黃素,腦啡??,多羥基薑黃素衍生物,去甲基薑黃素衍生物, | zh_TW |
| dc.subject.keyword | Alzheimer disease,Aβ,amyloid,curcumin,neprilysin,polyhydroxycurcuminoid,demethylated curcuminoid, | en |
| dc.relation.page | 117 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-01-27 | |
| 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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