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姓名	林明申(Ming-Shen Lin)  查詢紙本館藏	畢業系所	化學工程與材料工程學系
論文名稱	類澱粉胜肽與細胞膜交互作用機轉之動力學及熱力學研究 (The mechanism of beta-amyloid and cell membrane interactionby kinetics and thermodynamics analyses)
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摘要(中)	阿茲海默症是最常見的一種漸進式腦神經退化疾病，在病理學上的特徵是神經細胞外的類澱粉胜肽堆積，被認為是造成阿茲海默症的主因。然而AD的致病機轉至今仍有許多爭議，並無有效地治癒藥物與策略。為了明白類澱粉胜肽導致神經細胞死亡的機制，因此提出『Recruiting Hypothesis』，用來描述類澱粉胜肽與細胞膜之間交互作用機轉。 本研究為了驗證『Recruiting Hypothesis』，利用實驗設計分別以動力學及熱力學分析Aβ在溶液中聚集機轉及Aβ與人工合成脂膜交互作用，最終再以動物細胞模式驗證Aβ與類神經細胞(PC12)之交互作用。 (1) Aβ在溶液中聚集機轉： Aβ在溶液中是以random coil結構存在，在聚集的過程中Aβ的結構會由random coil轉變為β-sheet，且Aβ是以疏水作用力來穩定β-sheet之二級結構。另，Aβ聚集的動力學分析發現成核反應為Aβ聚集的速率決定步驟；而成核反應主要是以疏水作用力主導。在離子強度效應會導致Aβ具有相異的反應機制，形成不同型態的Aβ聚集體。 (2) Aβ與人工合成脂膜交互作用： Aβ與細胞膜作用會加速Aβ聚集形成纖維狀。Aβ在生理環境中會以靜電作用被吸引到細胞膜表面，隨後誘發GM1與膽固醇聚集形成raft-like。當中的Aβ會調整其構型為β-sheet，並吸引溶液中其他的Aβ聚集。最後raft-like間彼此聚集，形成富含Aβ、GM1及膽固醇的相，因此造成細胞膜不穩定，導致細胞功能降解甚至死亡。 (3) Aβ與類神經細胞(PC12)之交互作用： Aβ的細胞毒性隨著Aβ的濃度與C端序列長度增加；fresh Aβ在與PC12細胞作用時，較纖維狀的Aβ有較高的細胞毒性。降低細胞膜中膽固醇及GM1含量能夠有效地降低Aβ細胞毒性。由Aβ與PC12交互作用的熱量分析，也得到與細胞活性分析相符合的結果。 研究結果與文獻報導都支持所提出的『Recruiting Hypothesis』。因此，可藉由『Recruiting Hypothesis』中對Aβ與細胞膜間交互作用行為的描述，設計出治療AD的策略或藥物。另，研究中利用ITC即時地偵測Aβ與細胞交互作用時，PC12細胞的代謝熱量變化。此生物熱力學量測的方法具有快速且直接量測等優點，可用來觀測藥物/生物分子與活體細胞交互作用的熱量變化，甚至可得到細胞生理學的有益資訊，是極具發展潛力的偵測方法。
摘要(英)	AD is the most common neurodegenerative disease. The pathological hallmark of extra-cellular β-amyloid (Aβ) deposit is considered as one of the primary factors in inducing Alzheimer’s disease (AD). However, the mechanism of Aβ deposition on the cell membrane and the induced cytotoxicity is still unclear. The major obstacle in designing an effective therapeutic or strategy lies in our incomplete understanding of the mechanism of AD. On the basis of the previous reports and results, the “Recruiting Hypothesis” was proposed on the interaction between the plasma membrane and Aβ. For “Recruiting Hypothesis” verification , this study is analyzed by kinetic and thermodynamic methods which divided into three parts which shown as follows. (1) Investigation of the mechanism of beta-amyloid fibril formation In the aggregation process, the secondary structure of Aβ (1-40) transforms to the β-sheet conformation, which could be described as a two-state model. As the temperature and ionic strength increase, the conformation of Aβ converts to the β-sheet structure with an increased rate. Results of circular dichroism monitoring demonstrate that the rate constant of nucleation is smaller than that of elongation, and the nucleation is the rate-determining step during the overall Aβ aggregation. The β-sheet structure was stabilized by hydrophobic force as revealed by the ITC measurements. The different structural aggregates and forming pathways could be identified and discriminated at high and low ionic strengths, resulting in distinctive fibril conformations. Furthermore, the thermodynamic analysis shows that hydrophobic interaction is the major driving force in the nucleation step. (2)Studying the interaction between beta-amyloid and artificial cell membranes Results from SPR and lipid monolayer trough studies showed that the rate of Aβ adsorption onto lipid monolayer/liposome is mainly due to the electrostatic effect which is sensitive to the lipid monolayer/liposome composition. Due to the electrostatic attraction of more number of GM1 by the Aβ leads to the formation of GM1 clusters. The GM1 clusters incurred cholesterol recruitment and form raft-like structure Consequently, the Aβ conformation changed to β-sheet, which acts as a seed and initiates a chain reaction, in that it attract other Aβs to interact with the GM1. This resulted in the accumulation of Aβ on the plasma membrane. At the same time, both GM1 and cholesterol accumulate more and form larger clusters. Finally, each clusters aggregate with each other and form Aβ, GM1 and cholesterol rich phase which resulted in the function of membrane degradation. (3)Examining the interaction between beta-amyloid and PC12 cell Monomeric Aβ could attack the plasma membrane resulting in cytotoxicity, however, fibrillar Aβ was found to be less toxic. Aβ (1-40) was more toxic than Aβ (25-35) and the cytotoxcity of Aβ was proportional to its concentration. Besides, the depletion of GM1 from plasma membrane, it would block the Aβ-induced cytotoxicity. Decreasing the cholesterol level by around 30 % could attenuate the cytotoxicity of Aβ. These findings validate our idea that the cholesterol could stabilize the lateral pressure derived from the formation of GM1-Aβ complex on the membrane surface. Furthermore, both GM1 and cholesterol are essential in mechanism of Aβ accumulation and could modulate the cytotoxicity of monomeric Aβ. All these results list above and published references are support “Recruiting Hypothesis”. Understanding the insight of the interaction between Aβ and cell membrane which provide by “Recruiting Hypothesis” could be helpful in developing medicines and strategies aimed to cure AD. In addition, a biothermodynamic approach to real-time monitor the heat of metabolism by isothermal titration calorimetry (ITC) during PC12 cell-Aβ (1-40) interaction was provided by this study. This approach with rapid and directly measurement may provide not only real-time information for the interaction between Aβ and live cell but also more options for candidate drug development.
關鍵字(中)	★ 代謝熱量。 ★ 膽固醇 ★ Recruiting Hypothesis ★ 阿茲海默症 ★ 類澱粉胜肽	關鍵字(英)	★ Alzheimer’s disease ★ beta-amyloid ★ Recruiting Hypothesis ★ cholesterol ★ heat of metabolism.
論文目次	目 錄 中文摘要 IV ABSTRACT VI 致謝 IX 目錄 X 圖目錄 XIII 表目錄 XVIII 一、序論 1 1.1研究動機 1 1.2 Recruiting Hypothesis 3 1.3研究目的 5 二、文獻回顧 6 2.1阿茲海默症 6 2.1.1阿茲海默症病理特徵 6 2.1.2阿茲海默症臨床分類 9 2.2類澱粉前驅蛋白形成類澱粉蛋白的過程 9 2.3類澱粉胜肽的結構與細胞毒性 11 2.4類澱粉胜肽聚集的機轉 13 2.5類澱粉胜肽聚集動力學 17 2.6影響類澱粉胜肽聚集之因素 19 2.6.1類澱粉胜肽序列 19 2.6.2類澱粉胜肽濃度 20 2.6.3培養溫度 24 2.6.4緩衝溶液酸鹼值 26 2.6.5離子強度 28 2.6.6類澱粉胜肽的初始溶劑效應 30 2.6.7其他因素 33 2.7類澱粉胜肽與細胞膜交互作用 34 2.7.1生物細胞膜組成對Aβ聚集的影響 34 2.7.2類澱粉胜肽與細胞膜交互作用之動力學研究 41 2.7.3類澱粉胜肽與細胞膜交互作用之熱力學研究 43 2.7.4類澱粉胜肽與脂質單分子層交互作用 45 2.8阿茲海默症治療現況 51 三、材料與方法 53 3.1實驗藥品 53 3.2實驗儀器 55 3.3研究架構 56 3.4類澱粉胜肽在溶液中聚集機制 57 3.4.1類澱粉胜肽製備 57 3.4.2圓二色光譜儀量測類澱粉胜肽二級結構 57 3.4.3Thioflavin T 螢光偵測類澱粉胜肽β-sheet結構 57 3.4.4原子力顯微鏡量測類澱粉胜肽表面形貌 57 3.4.5恆溫滴定微卡計量測Aβ聚集反應焓 58 3.5類澱粉胜肽與人工合成脂膜交互作用 59 3.5.1類澱粉胜肽與脂質單分子層交互作用 59 3.5.2類澱粉胜肽與微脂粒交互作用 60 3.6類澱粉胜肽與類神經細胞交互作用 62 3.6類澱粉胜肽製備 62 3.6.2細胞培養與類澱粉胜肽作用 62 3.6.3降低細胞膜中GM1的含量 62 3.6.4調整細胞膜中膽固醇的含量 63 3.6.5細胞活性測試 63 3.6.6ITC量測Aβ與PC12細胞交互作用焓 64 3.6.7流式細胞儀分析細胞週期及細胞凋亡 65 四、結果與討論 67 4.1類澱粉胜肽在溶液中聚集機轉 67 4.1.1溫度效應 67 4.1.2酸鹼值效應 73 4.1.3離子強度效應 77 4.1.4 Aβ(1-40)分子間交互作用之熱力學分析 82 4.1.5 Aβ聚集機制分析 85 4.2類澱粉胜肽與人工合成脂膜交互作用 87 4.2.1類澱粉胜肽與脂質單層膜交互作用 87 4.2.2類澱粉胜肽與微脂粒交互作用 101 4.2.3 類澱粉胜肽與細胞膜交互作用分析 125 4.3 Aβ與PC12細胞之交互作用 127 4.3.1 Aβ的序列、構形及濃度對細胞毒性的影響 127 4.3.2 GM1對Aβ細胞毒性之影響 128 4.3.3膽固醇調控Aβ細胞毒性 128 4.3.4 ITC量測類澱粉胜肽與PC12細胞交互作用熱 136 五、結論與展望 150 參考文獻 153 附錄 182 圖目錄 圖1.1近二十年來，AD及amyloid相關的研究發表調查 2 圖1.2 Recruiting Hyphothesis示意圖 4 圖2.1阿茲海默症主要的病理特徵：神經細胞外的老化斑塊與神經細胞上的神經纖維糾結 8 圖2.2類澱粉前驅蛋白經酵素水解形成類澱粉蛋白的過程示意圖 11 圖2.3單體Aβ聚集形成纖維結構的示意圖 15 圖2.4 Aβ聚集形成fibril過程中產生反應中間體的示意圖 16 圖2.5 Aβ聚集形成fibril反應動力學 16 圖2.6 不同序列之Ab於不同培養時間的AFM形貌圖 21 圖2.7利用CD所測得Aβ(25-35)於pH 4.0環境下不同濃度時圖譜變化 22 圖2.8 不同濃度之Aβ(1-42)隨時間變化之AFM形貌圖 23 圖2.9 Aβ（1-42）於不同溫度培養24 hr之AFM形貌圖 25 圖2.10 Aβ於不同pH環境下的TEM形貌圖 27 圖2.11 Aβ(1-42)於不同pH環境下培養24小時的AFM形貌圖 27 圖2.12 Aβ(1-40)於（A）0 mM NaCl（B）150 mM NaCl環境下培養19小時的TEM形貌圖 29 圖2.13 Aβ(1-42)於（A）0 mM NaCl與（B）150 mM NaCl環境下培養24小時的AFM形貌圖 29 圖2.14 Aβ(1-40) protofibrils於150 mM NaCl環境下培養19小時的（A）AFM與（B）TEM形貌圖 30 圖2.15 Aβ(1-42)於不同初始溶劑下培養的形貌圖 32 圖2.16 glycospingolipids的結構 38 圖2.17以GM1為介質，促進Aβ形成纖維狀(fibril)的示意圖 39 圖2.18螢光標定PC12細胞上的GM1與Aβ；同一濃度的Aβ與PC12細胞作用，隨時間增加Aβ的量增多，且Aβ鍵結在PC12上的位置與GM1重合，但若把膽固醇移除可以發現Aβ沒有生成，且GM1很均勻分佈於細胞中，表示細胞中GM1與膽固醇的存在對於Aβ鍵結在細胞上為重要的因素 40 圖2.19 ITC可以配合CD的數據來探討胜肽在生物細胞膜上的作用機制 44 圖2.20 初始壓力固定時，蛋白質溶液注入後其表面壓隨時間的變化圖 47 圖2.21光探針的化學結構與位於POPC脂單層膜的位置，由下分別是laurdan、TMA-DPH、DPH 49 圖3.1 ITC量測Aβ與PC12細胞交互作用焓之示意圖 66 圖4.1 (A) Aβ培養於45 ?C時，隨時間偵測二級結構的變化之CD譜圖。(B) Aβ在30 , 37, 45 ?C培養24小時後的CD譜圖。(C) 隨時間偵測在30 ?C (?), 37 ?C (?), 45 ?C (?)培養溫度下，波長218 nm的橢圓率變化 70 圖4.2 ThT螢光偵測Aβ於30 ?C (?), 37 ?C (?), 45 ?C (?)培養時，隨時間生成纖維結構 71 圖4.3 AFM偵測35 μM的Aβ(1-40)在pH 7.4含有100 mM NaF的PBS中，培養24小時的形貌圖 72 圖4.4 pH值對Aβ培養在37 ℃生成fibril動力學的影響 75 圖4.5 ThT螢光隨時間偵測Aβ於pH 5.0 (?), 6.0 (?), 7.4 (?)，纖維結構的生成 76 圖4.6隨時間偵測在含有0 mM (?), 100 mM (?), 200 mM (?) NaF的緩衝溶液中，波長218 nm的橢圓率變化 79 圖4.7 ThT螢光隨時間偵測Aβ在含有0 mM (?), 100 mM (?), 200 mM (?) NaF的緩衝溶液中，纖維結構的生成 80 圖4.8 AFM偵測35 μM的Aβ(1-40)培養在37 ℃、pH 7.4的PBS中，培養24小時的形貌圖 81 圖4.9 培養溫度對單體Aβ與aggregated Aβ稀釋熱的影響 83 圖4.10 鹽濃度對單體Aβ稀釋熱的影響 84 圖4.11 Aβ吸附至DPPC/Chol.脂質單層膜的表面壓-時間等溫吸附曲線(Π-t isotherm) 90 圖4.12 Aβ與DPPC脂質單層膜交互作用的特徵時間示意圖 91 圖4.13 Aβ吸附於不同組成分的脂質單分子層之時間-表面壓等溫吸附曲線，25℃ 92 圖4.14 Aβ(1-40)吸附於DPPC/DPPG/Chol. (5/2/3)脂質單層膜之等溫線吸附線與膽固醇隨時間聚集的圖形 96 圖4.15 Aβ(1-40)吸附於DPPC/Chol.(7/3)脂質單層膜之等溫線吸附線與膽固醇隨時間聚集的圖形 97 圖4.16 當Aβ與DPPC/DPPG/Chol. (5/2/3)脂質單層膜反應時，膽固醇分子在負電脂質單層膜中的運動軌跡 98 圖4.17 當Aβ與DPPC/Chol. (7/3)脂質單層膜反應時，膽固醇分子在中性脂質單層膜中的運動軌跡 99 圖4.18 膽固醇在脂質單層膜中聚集面積之統計分析 100 圖4.19 20 μM的單體Aβ(1-40)與微脂粒交互作用之表面電漿共振感應圖 106 圖4.20 固定在SPR晶片的負電微脂粒與單體Aβ反應後，微脂粒遭到破壞之AFM表面形貌圖 107 圖4.21 固定在SPR晶片的中性微脂粒與單體Aβ反應後，微脂粒仍保持完整的形態 108 圖4.22 20 μM的聚集體Aβ(1-40)與微脂粒交互作用之表面電漿共振感應圖 109 圖4.23 20 μM的單體Aβ(1-40)與DPPC共同培養於25?C, pH7.4的10mM PBS 中，隨時間偵測二級結構變化之CD譜圖 114 圖4.24 20 μM的單體Aβ(1-40)與中性微脂粒共同培養，固定波長在218 nm隨時間偵測β-sheet結構變化 115 圖4.25 20 μM的單體Aβ(1-40)與DPPC/DPPG(5/3)微脂粒共同培養，Aβ的二級結構隨時間變化 116 圖4.26 20 μM的單體Aβ(1-40)與DPPC/DPPG/Chol.(5/2/3)微脂粒共同培養，Aβ的二級結構隨時間變化 117 圖4.27 20 μM的單體Aβ(1-40)與DPPC/GM1/Chol.(5/2/3)微脂粒共同培養，Aβ的二級結構隨時間變化 118 圖4.28 隨時間分別偵測單體Aβ(1-40)與(DPPC/DPPG/Chol.(5/2/3)及DPPC/GM1/Chol.(5/2/3)微脂粒培養在25 ?C，在波長218 nm的橢圓率變化 119 圖4.29 Aβ與微脂粒交互作用過程示意圖 121 圖4.30 單體Aβ(1-40)與不同組成份的微脂粒交互作用的反應熱 124 圖4.31 fresh Aβ濃度及胺基酸片段長度對細胞活性的影響 131 圖4.32 Aβ構形對細胞活性的影響 132 圖4.33 在細胞膜中GM1含量對Aβ(1–40)細胞毒性的影響 133 圖4.34 降低細胞膜中膽固醇含量對細胞活性的影響 134 圖4.35 在細胞膜中膽固醇含量對Aβ(1–40)細胞毒性的影響 135 圖4.36 Aβ(1-40)的構形對PC12細胞生長代謝熱量的影響 141 圖4.37 Aβ(1-40)的構形對PC12細胞活性的影響 142 圖4.38 隨時間偵測Aβ(1-40)對PC12細胞週期的影響 143 圖4.39 隨時間偵測Aβ(1-40)對PC12的細胞毒性 144 圖4.40 寡聚體的Aβ(1-40)濃度對PC12細胞生長代謝熱量的影響 145 圖4.41降低GM1含量的PC12細胞與寡聚體Aβ反應，隨時間偵測反應熱量 146 圖4.42 降低GM1濃度的PC12細胞與濃度為11 μM的寡聚體Aβ(1-40)反應12、24、48小時的細胞活性 147 圖4.43 調整PC12細胞的膽固醇含量與寡聚體Aβ反應，隨時間偵測反應熱量 148 圖4.44 調整膽固醇含量的PC12細胞與濃度為11 μM的寡聚體Aβ(1-40)反應12、24、48小時的細胞活性 149 表目錄 表2. 1 動物組織中細胞膜表面的脂質組成 37 表2. 2 Aβ對生物細胞膜流動性的影響 50 表4. 1 Aβ(1-40)在不同培養溫度之聚集動力學參數 73 表4. 2 Aβ與不同組成分的脂質單分子層交互作用之特徵時間τ1及τ2 93 表4. 3 Aβ與不同組成分的微脂粒交互作用 105 表4. 4 利用Langmuir binding model分析單體及聚集體的Aβ(1-40)與不同組成的微脂粒作用之親和力參數(KA) 105 表4. 5 單體Aβ(1-40)與微脂粒反應24小時，Aβ(1-40)二級結構的變化 113
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指導教授	陳文逸(Wen-Yih Chen)	審核日期	2010-1-25
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