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研究生: 李欣穎
Lee, Shin-Ying
論文名稱: 降低Aβ聚集導致阿茲海默氏症之新穎甘草查爾酮A與香豆素之衍生物的藥物開發
Development of novel licochalcone A and coumarin derivatives to mitigate the amyloid beta aggregation-induced Alzheimer’s disease
指導教授: 李桂楨
Lee, Guey-Jen
學位類別: 碩士
Master
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: 中文
論文頁數: 94
中文關鍵詞: 阿茲海默氏症β-澱粉樣蛋白查爾酮-香豆素雜合物抗氧化抗凋亡
英文關鍵詞: Alzheimer’s disease, amyloid β, chalcone-coumarin hybrid, anti-oxidation, anti-apoptosis
DOI URL: https://doi.org/10.6345/NTNU202201995
論文種類: 學術論文
相關次數: 點閱:114下載:11
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  • 阿茲海默氏症(Alzheimer's disease,簡稱AD),是老年癡呆症中最普遍的類型,臨床症狀包括漸進性認知功能下降以及長期記憶損傷。阿茲海默氏症的病理特徵主要可分為細胞外β-澱粉樣蛋白(β-Amyloid,簡稱Aβ)聚集形成的澱粉樣蛋白斑塊(Amyloid plaque),以及細胞內過度磷酸化tau蛋白形成的神經纖維纏結(Neurofibrillary tangles,簡稱NFTs)。Aβ斑塊造成神經細胞死亡的途徑包括氧化壓力提升、細胞外毒性、能量耗損以及細胞凋亡等,因此新Aβ聚集抑制劑的開發對於阿茲海默氏症的治療十分重要。甘草查爾酮A (Licochalcone A)及香豆素(Coumarin)為來自植物的天然化合物,具增強粒線體新生及/或抗氧化的功能。為了改善甘草查爾酮A及香豆素對阿茲海默氏症的可能治療效果,先前的研究透過化學修飾合成五種可抑制第三型小腦萎縮症polyQ蛋白聚集及幫助tau蛋白摺疊的衍生物。本研究首先以生化實驗檢測甘草查爾酮A、香豆素及五種合成衍生物捕捉自由基及抑制Aβ 聚集之能力。接著利用誘導表現Aβ-GFP之293/SH-SY5Y細胞,檢測待測化合物降低Aβ錯誤折疊及神經保護作用。在檢測的化合物中,衍生物LM-031細胞毒性最低,且具有自由基捕捉能力及Aβ聚集抑制能力,並可降低Aβ-GFP 293細胞中Aβ的錯誤折疊及相關的活性氧化物、凋亡蛋白酶-3活性,及促進Aβ-GFP SH-SY5Y細胞神經突生長。LM-031、甘草查爾酮A及香豆素可增強熱休克蛋白HSPB1表現,來增加Aβ-GFP融合蛋白溶解度,並正調控轉錄因子NRF2,來促進抗氧化反應元件依存的NQO1及GCLC表現。此外,在Aβ-GFP SH-SY5Y細胞中,LM-031、甘草查爾酮A及香豆素皆可增加與細胞存活、生長及/或抗凋亡相關因子的表現,如腦源性神經滋養因子BDNF、cAMP效應元件結合蛋白CREB、B细胞淋巴瘤蛋白-2 BCL2、胞外訊息調節激酶(ERK) 1/2、AKT絲胺酸/蘇胺酸激酶1 (AKT)等。本研究結果顯示甘草查爾酮A、香豆素及新穎查爾酮-香豆素雜合物LM-031可降低Aβ聚集及神經保護,提供臨床上阿茲海默氏症治療新的參考策略。

    關鍵字:阿茲海默氏症,β-澱粉樣蛋白,查爾酮-香豆素雜合物,抗氧化,抗凋亡。

    Alzheimer's disease (AD), the most common type of dementia in humans, is characterized as a progressive decline in cognitive function and loss of the long-term memory. The prominent pathological features of AD are aggregation of β-amyloid (Aβ) peptide in plaques and hyperphosphorylated tau protein in neurofibrillary tangles (NFTs). The Aβ deposition causes neuronal death via mechanisms including oxidative stress, excitotoxicity, energy depletion and apoptosis. Therefore, identifying novel Aβ aggregate inhibitor is essential to the disease treatment. Licochalcone A and coumarin are two natural compounds from plants with enhancing mitochondrial biogenesis and/or antioxidant activity. To improve therapeutic effects of licochalcone A and coumarin, chemical modification was applied and five licochalcone A and/or coumarin derivatives inhibiting SCA3 polyQ aggregation and reducing tau misfolding were obtained. In this study, biochemical tests were firstly used to examine the free radical scavenging and Aβ aggregation inhibition activities of licochalcone A, coumarin and the five synthetic derivatives. Tet-On Aβ-GFP 293/SH-SY5Y cells were then used to examine the ability of the tested compounds to reduce Aβ misfolding and neuroprotection. Among the tested compounds, derivative LM-031 had the lowest cytotoxicity and displayed the potentials of radical-scavenging and Aβ aggregation inhibition in biochemical tests, in addition to reducing Aβ misfolding and associated reactive oxygen species and caspase-3 activity in Aβ-GFP 293 cells and promoting neurite outgrowth in Aβ-GFP SH-SY5Y cells. LM-031, licochalcone A and coumarin enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase the solubility of Aβ-GFP fusion protein and upregulated nuclear factor erythroid 2-like factor 2 (NRF2) to promote antioxidant-responsive element-dependent NAD(P)H quinone dehydrogenase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC) expression. The expression of factors involved in cell survival, growth and anti-apoptosis, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), B-cell leukemia protein 2 (BCL2), extracellular signal-regulated kinase (ERK) 1/2, and AKT serine/threonine kinase 1 (AKT) were also increased in Aβ-GFP SH-SY5Y cells by LM-031, licochalcone A and coumarin. The study results demonstrated that licochalcone A, coumarin and novel chalcone-coumarin hybrid LM-031 are likely to work in Aβ aggregation reduction and neuroprotection, providing insight into the possible application in AD treatment.

    Keywords: Alzheimer’s disease, amyloid β, chalcone-coumarin hybrid, anti-oxidation, anti-apoptosis.

    目錄 目錄 I 中文摘要 IV Abstract VI 圖表次 VIII 壹、 緒論 1 一、 阿茲海默氏症(Alzheimer's disease) 1 二、 Amyloid-β (Aβ)胜肽 2 三、 HSPB1、Aβ聚集與阿茲海默氏症 4 四、 乙醯膽鹼、乙醯膽鹼脂酶及乙醯膽鹼脂酶抑制劑 5 五、 NRF2、抗氧化壓力與阿茲海默氏症 6 六、 CREB、神經生長與阿茲海默氏症 7 七、 甘草查爾酮A (Licochalcone A)、香豆素(Coumarin)及待測化合物 10 八、 藥物篩檢研究 12 貳、 研究目的 14 參、 研究材料與方法 15 一、 DPPH自由基清除能力檢測 15 二、 Thioflavin T 螢光亮度檢測 15 三、 細胞培養與繼代 16 四、 化合物毒性測試 16 五、 Aβ-GFP細胞模式螢光亮度照相 17 六、 Aβ-GFP細胞模式篩檢 17 七、 Aβ-GFP細胞模式毒性測試 18 八、 Aβ-GFP 細胞模式Aβ-GFP RNA表現量檢測 18 九、 活性氧化物檢測 19 十、 凋亡蛋白酶-3活性檢測 20 十一、 神經突生長觀測 21 十二、 乙醯膽鹼脂酶活性測試 22 十三、 西方轉漬法 23 十四、 統計分析 25 肆、 結果 26 一、 DPPH自由基清除能力分析 26 二、 Thioflavin T 螢光分析 26 三、 待測化合物細胞毒性分析 27 四、 正控制組薑黃素的Aβ-GFP 293細胞分析 27 五、 待測化合物的Aβ-GFP 293細胞篩檢分析 28 六、 待測化合物Aβ-GFP 293細胞毒性分析 29 七、 化合物處理Aβ-GFP293細胞模式的Aβ-GFP RNA表現量 分析 30 八、 活性氧化物分析 31 九、 凋亡蛋白酶-3活性分析 31 十、 神經突生長分析 32 十一、 凋亡蛋白酶-3蛋白表現量分析 33 十二、 乙醯膽鹼脂酶活性分析 34 十三、 NRF2與下游抗氧化壓力蛋白表現量分析 35 十四、 CREB與下游神經生長相關蛋白表現量分析 37 伍、 討論 40 陸、 參考文獻 50 柒、 附錄圖表 72

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