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研究生：	黃頂翔 Huang, Ding-Siang
論文名稱：	脊髓小腦萎縮症第十七型及阿茲海默氏症神經保護中草藥的研究 Neuroprotective Chinese herbal medicines against polyQ-mediated spinocerebellar ataxia type 17 and Alzheimer’s disease
指導教授：	吳忠信 Wu, Chung-Hsin 林榮耀 Lin, Jung-Yaw
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	78
中文關鍵詞：	中草藥、脊髓小腦萎縮症第十七型、興奮性毒性、多麩醯胺疾病、細胞凋亡、阿茲海默氏症、三重阿茲海默氏症基因轉殖小鼠、神經保護
英文關鍵詞：	Chinese herbal medicine, spinocerebellar ataxia type 17, polyQ diseases, excitotoxicity, Alzheimer’s disease, apoptosis, triple transgenic AD mice, neuroprotection
DOI URL：	https://doi.org/10.6345/NTNU202202215
論文種類：	學術論文
相關次數：	點閱：186 下載：7
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多麩醯胺（PolyQ）介導的神經退行性疾病是由各種蛋白質的多麩醯胺擴增引起的。而脊髓小腦萎縮症第十七型（SCA 17）是由TATA盒結合蛋白（TATA box-binding protein, TBP）基因中CAG / CAA重複擴增引起的多麩醯胺疾病。銀杏葉提取物EGb 761含有黃酮和萜類化合物，可用於治療神經退化性疾病如阿茲海默氏症與帕金森氏病。雖然EGb 761的神經保護作用的功能已經被證實，但是EGb 761對於治療SCA 17是否具有效果則尚不清楚。為解決此一問題，我們利用表達TBP/79Q的SH-SY5Y細胞，以及具有人類突變型TBP基因的SCA17轉基因小鼠進行實驗。我們的研究成果發現利用EGb 761處理TBP/79Q-SH-SY5Y細胞後，細胞內十二烷基硫酸鈉不溶性蛋白質的含量會明顯減少；我們進一步發現，EGb 761處理可以抑制TBP/79Q-SH-SY5Y細胞的興奮性毒性以及鈣離子流入，並且降低經麩醯胺酸鹽處理SH-SY5Y神經母細胞瘤細胞的細胞凋亡標誌物表達。活體實驗中，我們每天利用腹腔內注射EGb 761（100 mg/kg）給予SCA 17轉基因小鼠，實驗結果發現EGb761可以有效緩解SCA 17轉基因小鼠的運動缺陷。由上述研究結果提供證據證實利用SCA 17的細胞與轉基因小鼠模型，EGb 761可以通過抑制神經細胞的興奮性毒性和細胞凋亡來達到治療SCA 17的效果。為此，我們認為EGb 761可能是有效治療SCA 17的潛在治療藥物。除罕見的遺傳性SCA 17外，阿茲海默氏症（AD）是最常見的神經退化性疾病，AD特徵在於受影響腦區域中形成澱粉樣蛋白-β肽的胞外斑塊，以及細胞內微管相關蛋白tau因為過度磷酸化聚集形成的神經原纖維纏結。在本研究中，我們探討X蛋白質對於乙型類澱粉蛋白聚合的影響，我們也發現綠茶內的其中一種茶多酚，Epigallocatechin gallate (EGCG) 能抑制X蛋白質對於乙型類澱粉蛋白的聚合作用，亦能增加細胞存活率。此外經過EGCG處理的三重轉基因AD小鼠（h-APPSwe，h-tauP301L和h-PS1M146V），通過Morris水迷宮、Y迷宮和新穎的對象識別的動物行為測試實驗，發現轉基因AD小鼠的記憶學習均獲得顯著的改善。因此，我們認為EGCG可能透過抑制X蛋白質而有效治療AD的多功能潛在治療藥物。

Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats (> 43 repeats) in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extracts EGb 761 contain flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Parkinson's disease, but whether the EGb 761 has therapeutic effects in SCA 17 are still unclear. To investigate our issues, we have generated TBP/79Q-expressing SH-SY5Y cells, and SCA 17 transgenic mice with the mutant hTBP gene. In vitro experiment, we observed that the EGb 761 treatment decreased the amount of sodium dodecyl sulfate-insoluble proteins in the TBP/79Q-expressing SH-SY5Y cells. We further found that the EGb 761 treatment could inhibit excitotoxicity and calcium influx, and reduce the expression of apoptotic markers in glutamate-treated SH-SY5Y neuroblastoma cells. In vivo experiment, we observed that the EGb 761 treatment (100 mg/kg intraperitoneally injection every other day) could relieve the motor deficiencies of the SCA 17 transgenic mice. Our findings provide evidence that the EGb 761 treatment can remedy for SCA 17 via suppressing excitotoxicity and apoptosis in SCA 17 cells and animal models. Therefore, it indicates that EGb 761 could be a potential therapeutic agent for treating SCA 17.
Apart from rare inherited SCA 17, Alzheimer’s disease (AD) is the most common neurodegenerative disease and characterized by the formation extracellular plaques of the amyloid-β peptide and intracellular neurofibrillary tangles of hyperphosphorylated aggregates of microtubule-associated protein tau in affected brain regions. We examined the effects of epigallocatechin gallate (EGCG) on Aβ oliogmerization induced by protein X, and found that EGCG attenuated amyloidogenic pathway promoted by protein X. EGCG also increased the cell viability after Aβ treatment in SH-SY5Y/protein X cells. Furthermore, EGCG treatment improved the performance of triple transgenic AD mice (h-APPswe, h-TauP301L, and h-PS1M146V) in the Morris water maze, Y maze and novel object recognition test. Collectively, these results suggest that EGCG could be a promising multifunctional drug candidate for AD by inhibiting protein X.

CONTENTS
CONTENTS    I
LIST OF FIGURES    V
中文摘要    VII
ABSTRACT    IX

CHAPTER 1. GENERAL INTRODUCTION    1
1.1 Neurodegeneration    2
1.2 Chinese herbal medicines    2
1.3 Research aims    4

CHAPTER 2. PROTECTIVE EFFECTS OF EGb 761 AGAINST SPINOCEREBELLAR ATAXIA TYPE 17 BY INHIBITOION OF EXCITOXICITY PATHWAY    6
2.1 Introduction    7
2.2 Materials and Methods    9
2.2.1 Materials    9
2.2.2 Cell culture    10
2.2.3 Cell viability assay    10
2.2.4 Measurement of calcium influx    11
2.2.5 Western blot analysis    11
2.2.6 Dot blot assay    12
2.2.7 Animals    13
2.2.8 Rotarod performance    14
2.2.9 Immunohistochemistry (IHC)    15
2.2.10 Statistical analysis    16
2.3 Results    17
2.3.1 Effects of EGb 761 on glutamate-induced cytotoxicity    17
2.3.2 Inhibition effects of EGb 761 on calcium influx induced by glutamate    17
2.3.3 Inhibition effects of EGb 761 on glutamate-mediated cell apoptosis    18
2.3.4 EGb 761 suppresses TBP/79Q aggregation and apoptosis in the TBP/79Q-EGFP cells    19
2.3.5 EGb 761 ameliorates the motor function of the SCA 17 transgenic mice    20
2.4 Discussion    33
2.5 References    36

CHAPTER 3. PROTECTIVE EFFECTS OF EGCG AGAINST Αβ42 OLIGOMERIZATION INDUCED BY PROTEIN X    47
3.1 Introduction    48
3.2 Materials and Methods    50
3.2.1 Materials    50
3.2.2 Cell culture, construction of expression plasmids and transfection    50
3.2.3 Target identification using drug affinity responsive target stability (DARTS)    51
3.2.4 Thioflavin T assay    52
3.2.5 Pull down assay and western blot analysis    52
3.2.6 Dot-blot assay    53
3.2.7 Animals    53
3.2.8 Water maze test    54
3.2.9 Y maze task    54
3.2.10 Novel object recognition experiment    55
3.2.11 Statistical analysis    55
3.3 Results    56
3.3.1 Protein X interacts with Aβ42 and increases Aβ42 oligomerization    56
3.3.2 EGCG inhabits Protein X-induced Aβ42 oligomerization and fibrillization    56
3.3.3 Effects of EGCG on Aβ42 cytotoxicity that enhanced by protein X    57
3.3.4 EGCG ameliorates the memory deficits of 3xTg-AD mice    58
3.4 Discussion    68
3.5 References    70

APPENDIX    77
Table 1 Pathological features of neurodegenerative diseases    78

 
LIST OF FIGURES
Figure 1 EGb 761 increased cell viability after glutamate-induced excitotoxicity in SH-SY5Y cells    23
Figure 2 EGb 761 increased calcium influx after glutamate-induced excitotoxicity in SH-SY5Y cells    24
Figure 3 Treatment with EGb 761 downregulated apoptosis markers induced by glutamate    25
Figure 4 EGb 761 reversed mitochondrial dysfunction after glutamate induced excitotoxicity in SH-SY5Y cells    26
Figure 5 Suppression of protein aggregation by EGb 761 in the TBP/79Q-EGFP cells    27
Figure 6 Inhibitory effects of EGb 761 on apoptosis in TBP/79Q-EGFP cells    28
Figure 7 EGb 761 suppressed the TBP aggregation in the SCA 17 transgenic mice    29
Figure 8 Protective effects of EGb 761 in the SCA 17 transgenic mice    30
Figure 9 A schematic representation of protective effects of EGb 761 on SCA 17    32
Figure 10 Interaction between Aβ42 and protein X    60
Figure 11 EGCG Suppressed the A11 positive oligomers induced by protein X    61
Figure 12 Effects of EGCG on protein X-induced Aβ42 fibrillization    62
Figure 13 Effects of EGCG on Aβ42 cytotoxicity and Aβ42 oligomerization induced by protein X    63
Figure 14 EGCG alleviated the memory impairments in 3xTg AD mice    65
Figure 15 A schematic representation of effects of EGCG on amyloidogenic pathway induced by protein X    67
                                

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Ch. 3
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