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標題: | 膽固醇在APP蛋白質水解反應中所扮演的角色 The Role of Cholesterol in Aβ Precursor Protein Processing |
作者: | Ke-Ming Huang 黃可名 |
指導教授: | 孔繁璐(Fan-Lu Kung) |
關鍵字: | 膽固醇,APP蛋白,CRAC序列,lipid raft,C99/C83比值, cholesterol,APP protein,CRAC sequence,lipid raft,C99/C83 ratio, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 在阿茲海默氏症(Alzheimer’s disease, AD)的研究領域中,膽固醇與b-amyloid precursor protein (APP)蛋白之間的關係一直是個懸而未決之謎。膽固醇可能借由與APP蛋白有直接的交互作用,而促使APP蛋白走向產生導致阿茲海默氏症的Ab的水解途徑。為了要進一步探討膽固醇與APP蛋白之間的交互作用如何影響APP的水解,我們利用點突變的方式將APP蛋白上與膽固醇做辨認的cholesterol recognition amino acid consensus (CRAC)序列做突變,試著藉由突變產生無法與膽固醇有良好交互作用的APP突變型蛋白。實驗結果發現,APP突變型與lipid raft的標誌蛋白flotillin-1 共分層的程度比野生型來得少;APPY422L與APPS622L在經常用來評估引發致病水解途徑的C99/C83比值上,也較野生型來得低;更進一步的研究發現在去除了膜上的膽固醇後,和僅僅破壞膜上的raft構造,但膜上的膽固醇含量卻仍維持不變時相比,APP蛋白的分層情況並不相同。這些結果指出膽固醇與APP蛋白之間的交互作用力可能造成APP蛋白更容易散布進入lipid raft中,使得APP蛋白更有機會被BACE1水解酶水解,產生Ab片段。 The relationship between cholesterol and b-amyloid precursor protein (APP) processing remains an unsolved mystery in the Alzheimer’s disease (AD) research field. It has been hypothesized that there is a direct interaction between cholesterol and APP, which might facilitate APP being processed into Ab in its pathogenic pathway. To assess the importance of the APP-cholesterol in the regulating of regulating APP processing, we generated several cholesterol-binding-deficient APP mutant proteins via introducing mutations in the domains with the putative cholesterol recognition amino acid consensus (CRAC) sequence of APP. Our results revealed that a smaller portion of APP mutants was co-fractionated with the lipid raft marker flotillin-1 compared to wild-type APP. The C99/C83 ratio, which is usually used in evaluating pathogenesis processing level, is also reduced by Y422L and S622L mutations. Further study shows APP pattern in cholesterol-depleted cells was different from raft-disrupted cells in which the membrane cholesterol content remained unchanged. These data suggested that the interaction between cholesterol and APP could be a driving force for distributing APP into lipid raft, which makes APP more accessible to the pathogenically critical protein BACE1. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44430 |
全文授權: | 有償授權 |
顯示於系所單位: | 藥學系 |
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