利用螢光顯微鏡及單分子模型槽探討類澱粉胜肽與不同組成之脂質單分子膜之交互作用

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陳幸貝(Shing-Bei Chen) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

利用螢光顯微鏡及單分子模型槽探討類澱粉胜肽與不同組成之脂質單分子膜之交互作用
(Interaction Mechanism Studies Between β-Amyloid and Lipid Monolayer by Fluorescent Microscopy and Langmuir-Blodgett Trough)

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摘要(中)

於阿茲海默症相關之研究中，到目前為止Aβ（1-40）是如何引發細胞毒性及疾病的作用機制仍然不是很清楚，在本研究中吾人利用脂質單層膜及微脂粒與Aβ交互作用來探討Aβ與細胞膜的交互作用機制。為此本研究室提出ㄧ所謂“Recruiting Hypothesis＂假說來說明Aβ是如何與細胞膜作用進而毒殺神經細胞，此假說為：
1.單體Aβ與含有神經節苷酯的細胞膜以靜電作用力為主要之高度的親和力交互作用，吸附至細胞膜的表面。
2.而吸附於膜上的Aβ會暴露出其帶正電的胺基酸殘基與膜帶電脂質（如DPPG、GM1）作用，並調整構型形成α-helix結構。
3.形成α-helix的Aβ會以靜電作用力吸引神經節苷酯與神經節苷酯聚集，造成神經節苷酯的recruiting。
4.因為神經節苷酯的聚集造成細胞膜的側壓上升，所以誘發膽固醇也進行recruiting行為，以維持細胞膜壓力的穩定，所以形成局部團簇（raft-like）於細胞膜上。
5.位在團簇中的Aβ會改變其構型而形成β-摺疊板，並以種子的形式去吸引溶液中的Aβ與種子Aβ做用。
6.再誘發溶液中的Aβ至細胞膜的過程當中，同時也會recruiting更多的神經節苷酯及膽固醇去形成更大的團簇，造成Aβ聚集形成纖維狀。最後各個團簇彼此聚集，形成富含Aβ、神經節苷酯及膽固醇的相，細胞膜因此重新排列，造成局部缺少神經節苷酯及膽固醇進而導致細胞膜功能的降解。
　　為了要證明此假說，整個研究的主題分為兩個部份：第一部分是利用單分子模型槽（Langmuir-Blodgett Trough）探討單體的Aβ吸附於不同組成之脂質單層膜（monolayer）之時間-表面壓等溫吸附線來獲得動力學資訊。另針對假說的第四點，利用帶有螢光的膽固醇製備不同組成之脂質單層膜，來觀察單體的Aβ與不同組成之脂質單層膜交互作用後，利用螢光顯微鏡去觀察膽固醇的聚集行為。第二部份是利用CD（圓二色光譜儀）探討Aβ與不同組成之微脂粒交互作用隨時間之構型轉變，並輔以蛋白質二級結構分析軟體來分析Aβ各二級結構所佔含量，可以進ㄧ歩了解Aβ與微脂粒交互作用後隨時間構型轉變的行為。
　　由螢光顯微鏡實驗結果顯示Aβ與帶負電脂質及膽固醇之單層膜交互作用下，會誘發膽固醇的聚集行為。而從單分模型槽實驗及圓二色光譜儀實驗的結果皆證實GM1與膽固醇同時存在會加速Aβ構型轉變。由以上結果可以說明，Aβ分子ㄧ開始是以靜電作用力吸附於單分子層上，當吸附於單分子層表面後，調整其構型轉換為α-helix後會以靜電作用力吸引GM1與GM1聚集，且會造成細胞膜的側壓上升，所以在構型轉變時就需要膽固醇穩固膜壓，因此造成膽固醇的聚集，而位在膽固醇團簇中的Aβ會改變其構型而形成β-sheet結構。此結果證實了我們所提出的“Recruiting Hypothesis”。

摘要(英)

In the study of the Alzheimer’s Disease, the interaction mechanism between β-amyloid and cells are still not clear. In this study, we propose a“Recruiting Hypothesis”to investigate the interaction mechanism between Aβ & lipid monolayer. The hypothesis is that the adsorption of monomeric Aβ on the negative lipid and the conformation arrangement to form α-helical, the α-helical Aβ attach other negative lipid to form negative lipid cluster, as the negative lipid cluster induce the lateral rise in pressure of the membrane, cholesterol is recruited by the cell to form the raft-like structure to stabilize the pressure.
　　The objective of this research is to understand the interaction mechanism of β-amyloid (Aβ) with cell and this study is basically divided into two parts. First at all, the adsorption kinetics behaviors of Aβ on lipid monolayers were also studied by NIMA trough and we used the fluorescent-labeled cholesterol to investigate the behavior of cholesterol in membrane by fluorescent microscopy (FM). Secondary, we focused on the time -dependent structural changes of Aβ (1-40) which incubated in various liposome by circular dichroism (CD) spectroscopy.
　　Results from lipid monolayer trough studies showed that the rate of Aβ adsorbed onto lipid monolayer is mainly due to the electrostatic effect, and the structural rearrangements of the adsorbed Aβ is sensitive to the lipid monolayer composition. Results from the FM, the interaction of Aβ with lipid monolayer containing negative charge lipid and cholesterol brings out the recruiting behavior of the cholesterol. The variations of secondary structure of Aβ（1-40）incubated in various liposome by CD. The liposome with negative charge lipid may promote the α-helix formation; however, the β-sheet conformation was induced by the liposome with negative charge and cholesterol. The results are consistent with our “Recruiting Hypothesis”.

關鍵字(中)

★ 類澱粉胜肽
★ 膽固醇
★ 神經節苷酯
★ 阿茲海默症

關鍵字(英)

★ β-amyloid
★ Cholesterol
★ ganglioside
★ Alzheimer

論文目次

中文摘要 I
Abstract III
誌謝 V
目錄 VI
圖目錄 VIII
表目錄 XIV
第一章前言 1
第二章文獻回顧 4
2.1　阿茲海默症與類澱粉胜肽 4
2.1.1　阿茲海默症 4
2.1.2　類澱粉胜肽（β-amyloid，Aβ）8
2.1.3　類澱粉胜肽在不同環境下的結構及特性 10
2.2　Aβ與生物細胞膜之交互作用研究 23
2.2.1　Aβ與脂質單分子層之交互作用研究 23
2.2.2　Aβ對細胞膜流動性的影響 26
2.3　單分子模型槽 31
2.3.1　蛋白質於氣/液界面上的吸附行為 31
2.3.2　表面張力的定義與測量 31
2.3.3　單分子層（Monolayer） 34
2.4 圓二色光譜儀（Circular Dichroism，CD） 37
2.4.1　圓二色光譜儀測量原理 37
2.4.2　蛋白質或多胜肽的圓二色光譜 39
2.5　螢光顯微鏡（Fluorescence Microscopy） 41
2.5.1　螢光發光原理 41
2.5.2 螢光顯微鏡之特性 42
第三章實驗藥品與儀器設備 43
3.1　實驗藥品 43
3.2　儀器設備 44
3.3　實驗方法 44
3.3.1　緩衝溶液的配製 44
3.3.2 脂質單層膜的配製 45
3.3.3 微脂粒的製備【67】 45
3.3.4 類澱粉蛋白溶液的配製 46
3.3.5 單分子模型槽實驗 46
3.3.6 螢光顯微鏡取像實驗 47
3.3.7 圓二色光譜儀實驗 47
第四章　結果與討論 48
4.1 單分子模型槽實驗 48
4.1.1不同組成的脂質單分子層於氣/液界面上之Π-A 48
isotherm 48
4.1.2　Aβ（1-40）吸附於不同組成的脂質單分子層表面壓- 52
時間改變的等溫吸附線（Π-t isotherm） 52
4.1.2.1　單分子層初始表面壓為10mN/m 52
4.1.2.2　單分子層初始表面壓為15mN/m 56
4.1.2.3　單分子層初始表面壓為20mN/m 57
4.2 螢光顯微鏡實驗 62
4.3 圓二色光譜實驗 77
第五章　結論 92
第六章參考文獻 96

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指導教授

陳文逸(Wen-Yih Chen)

審核日期

2007-7-24

推文