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研究生:林錦萱
研究生(外文):Chin-Hsuan Lin
論文名稱:探討isovitexin抑制人類神經瘤母細胞SH-SY5Y中β-分泌酶表現之作用機轉
論文名稱(外文):Study of Inhibitory Mechanisms of Isovitexin on β-Site APP Cleaving Enzyme Expression in Human Neuroblastoma SH-SY5Y Cells
指導教授:蔡維人蔡維人引用關係楊行義楊行義引用關係
指導教授(外文):Wei-Jern TsaiHsing-Yi Yang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:102
中文關鍵詞:人類神經瘤母細胞
外文關鍵詞:Human Neuroblastoma
相關次數:
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  • 下載下載:27
  • 收藏至我的研究室書目清單書目收藏:1
中文摘要

阿茲海默氏症是引起老人失智最常見的一種神經退化疾病。而類澱粉樣胜肽前驅蛋白 amyloid precursor protein,APP) 被 β-分泌酶 (β-secretase,beta-site APP cleaving enzyme 1,BACE1 ) 切割產生了beta-cleaved C-terminal fragment (C99) 之後,再被γ-分泌酶 (γ-secretase) 切割,所產生的 β 澱粉樣胜肽 (amyloid β-peptide,Aβ) 會沉積在腦部組織,對阿茲海默氏症的病程發展扮演了非常重要的角色。其中BACE1對於 Aβ 的生成而言是速率限制酵素,且其酵素活性、mRNA 及蛋白質表現量在阿茲海默氏症病人身上都有增加的情形,因此 BACE1 被認為是很有潛力的治療目標。過去本實驗室經由已建立好的篩藥系統,篩選出具有潛力的BACE1 抑制劑,稱為 isovitexin。本篇研究即欲探討 isovitexin 抑制 BACE1 的可能藥理作用機轉。實驗結果顯示,isovitexin 無論是在人類血小板或是在人類神經瘤母細胞 SH-SY5Y 中對總蛋白質內的 BACE1 活性皆具有抑制作用。而在進入SH-SY5Y 細胞模式後也可以抑制 BACE1 切割產物 C99 以及細胞內外 Aβ 的生成,並且不會產生細胞毒性,表示其在活細胞內也可以抑制�nBACE1 的活性。此外也證明了isovitexin 主要是經由抑制BACE1 蛋白質表現量而抑制 C99 以及 Aβ 的產量。BACE1 蛋白質表現量的減少,可能來自於 isovitexin 會促進 BACE1 的分解 (degradation),或者是影響 BACE1 基因的表現。最後,也證實了 isovitexin 並不會促進 BACE1 的分解,但是會影響 BACE1 mRNA 的穩定性 (stability)。綜合上述,isovitexin可能經由影響BACE1 mRNA 的穩定性進而抑制了BACE1 蛋白質的表現量,但是也不排除可能有其他的機轉參與其中。
Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The processing of �namyloid precursor protein (APP) is initiated by beta-site APP cleaving enzyme 1 (BACE1) cleavage, which produce beta-cleaved C-terminal fragment (C99), and then further cleaved by γ-secretase leads to amyloid β-peptide (Aβ��)formation. Generation and deposition of Aβ is central to the aetiology of AD. Herein, BACE1 is a rate-limiting enzyme in the production of Aβ. Consequently, the enzyme activity, mRNA and protein levels of BACE1 are elevated in AD patients. So the inhibition of BACE1 is an attractive therapeutic target for the treatment of AD. Our previous BACE1 inhibitor screening model discovered that isovitexin is a potential BACE1 inhibitor. Therefore, the aim of this study is to evaluate possible pharmacologic inhibitory mechanisms of isovitexin on BACE1. The in vitro results showed that isovitexin suppressed BACE1 activity in human platelet and SH-SY5Y total protein. Isovitexin also inhibited BACE1 activity in SH-SY5Y cell model, since it indeed attenuated C99,intra- and extra- cellular Aβ���nproduction . The isovitexin did not obviously influence on cell viability. Besides, it major via inhibited BACE1 protein expression, thereby inhibited the production of C99 and Aβ. Lower expression of BACE1 protein maybe derive from isovitexin enhanced BACE1 degradation or attenuated BACE1 gene expression. This study also showed that isovitexin did not promote BACE1 degradation but influence on BACE1 mRNA stability. In summary, isovitexin probably inhibited BACE1 protein expression through interfere BACE1 mRNA stability, although other involved mechanisms were not excluded.
目錄

英文縮寫對照表………………………………………………………1
中文摘要………………………………………………………………4
英文摘要………………………………………………………………5
壹、緒論…………………………………………………………… 6
貳、研究動機與目的……………………………………………… 21
參、材料與方法…………………………………………………… 23
肆、實驗結果……………………………………………………… 30
伍、討論…………………………………………………………… 42
陸、參考文獻……………………………………………………… 49
柒、圖表…………………………………………………………… 62
捌、附錄…………………………………………………………… 96
陸、參考文獻

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