透過改變磷脂質排列密度減少Amyloid β與膜之間交互作用

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邱品銓(Pin-Chiuan Chiou) 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

透過改變磷脂質排列密度減少Amyloid β與膜之間交互作用
(REDUCING THE INTERACTION BETWEEN AMYLOID β AND MEMBRANE BY CHANGING LIPID PACKING DENSITY)

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摘要(中)

澱粉樣蛋白β（Aβ）胜肽是在患有阿茨海默症（AD）的大腦中，普遍存在的蛋白質斑塊主要成分，因此長期以來研究人員在為阿茨海默症開發有效的診斷和治療方法受到密切關注。雖然過去的研究集中在Aβ的聚集行為及其抑制，但最近的一些研究已經指出了在Aβ與神經膜之間致病相關性的相互作用，為相關的研究鋪平了道路。在這裡，為了解決許多關於Aβ與膜之間相互作用尚未解決的問題，我們採用由磷脂酰膽鹼和磷脂酰甘油組成的二元脂質體作為模型系統，並通過改變其脂質的鏈烴類型（即長度和飽和度）來調節其分子排列密度並調查膜的物理性質如何影響不同聚集狀態下膜與Aβ之間的相互作用。值得注意的是，雖然具有較不緊密和有序包裝的膜對由寡聚體Aβ（> 30kDa）誘導的結構干擾敏感，藉由形成類似孔狀結構，如用原子力顯微鏡（AFM）成像，但膜並不能通過Aβ與膜的相互作用輕易地被分解。相比之下，通過結合AFM、X光散射和螢光洩漏的測量顯示，具有更緊密且有序的脂質膜被Aβ變厚且容易被分解。這些發現表明膜的排列密度是Aβ與膜相互作用的關鍵決定因素。由於人類神經膜的脂質組成會隨著年齡的增長而變化，這樣的變化提高了膜的排列密度，據臨床觀察指出阿茨海默症發病率隨年齡急劇增加，我們的發現可能是構成此現象的起因。增加不飽和磷脂質的量或扭轉膜緊密排列的趨勢可能是對付阿茨海默症的一種方式。

摘要(英)

Amyloid β (Aβ) peptides are the major component of the proteinaceous plaques prevalent in the brains afflicted with Alzheimer′s disease (AD), and therefore have long drawn researchers’ close attention in their efforts to develop effective diagnostics and therapeutics for AD. While past researches had focused on the aggregation behavior of Aβ and its suppression, some very recent studies have pointed to the pathogenic relevance of the interactions between Aβ and neuronal membranes, thus paving a new way for the related researches. Here, to help address many unresolved questions regarding the Aβ-membrane interactions, we adopt the binary liposomes composed of phosphatidylcholine and phosphatidylglycerol as model systems and modulate their molecular packing densities by changing the types (i.e., lengths and saturation) of the hydrocarbon chains of the lipids to investigate how changes in the physical property of a membrane affect the interactions between the membranes and Aβ in different aggregation states. Remarkably, while the membranes with less tight and ordered packing are susceptible to the structural disturbances induced by oligomeric Aβ (>30 kDa), through the formation of pore-like structures, as imaged with the atomic force microscopy (AFM), the membranes cannot be disintegrated by the Aβ-membrane interactions with ease. In contrast, the membranes with the lipids packed more tightly and orderly are thickened and readily disintegrated by Aβ, as revealed by the X-ray scattering and fluorescent leakage assays combined with AFM, respectively. These findings demonstrate that the packing density of a membrane is a key determinant of the Aβ-membrane interactions. Since the lipid compositions of human neuronal membranes change with age, which raises the packing density of the membranes, our findings may underlie the clinical observation that the incidence of AD increases sharply with age. Increasing the amount of unsaturated phospholipid or even reversing the trend of tight packing of the membrane might constitute a way of fighting AD.

關鍵字(中)

★ 阿茲海默症
★ 類澱粉樣蛋白β
★ 螢光洩漏
★ 原子力顯微鏡
★ 排列密度

關鍵字(英)

★ Alzheimer′s disease
★ Amyloid β
★ Fluorescence leakage
★ AFM
★ Packing density

論文目次

摘要 I
Abstract II
致謝 IV
Table of Contents V
List of Figures VIII
List of Tables X
List of Equations XI
List of Abbreviations XII
Chapter 1 Introduction 1
1-1. Alzheimer′s Disease 1
1-1-1. Appearance of amyloid β and structural change 1
1-1-2. Pathogenic feature and correlation between neurons and protein 5
1-2. Membrane 6
1-2-1. Cell membrane 6
1-2-2. Phospholipid 8
1-3. Model Lipid Membranes 10
1-4. Packing Defect of Cell Membrane Induced Amyloid β Deposition 13
1-5. Motivation 14
Chapter 2 Materials and Methods 16
2-1. Materials 16
2-1-1. Phospholipid 16
2-1-2. Peptide 30
2-1-3. Non-biological materials 34
2-2. Sample Preparation 35
2-2-1. Preparation of liposome for AFM 35
2-2-2. Preparation of liposome containing fluorescence dye 37
2-2-3. Preparation of supported lipid bilayer 38
2-2-4. Preparation of peptides 41
2-2-5. Monolayer on Langmuir trough 43
2-3. Dynamic Light Scattering Measurement 44
2-4. Fluorescence Measurement 46
2-4-1. Leakage of fluorescence dye measurement 48
2-4-2. Thioflavin T assay of Aβ 52
2-5. Atomic Force Microscope Experiment 53
2-6. Langmuir Trough Measurement 54
2-7. Spectrum Measurement 57
2-7-1. Circular dichroism 57
2-7-2. Ultraviolet absorption method 60
2-8. Data Processing 62
2-8-1. Matlab 62
2-8-2. Origin 64
2-8-3. Model fitting by using fityk 65
2-8-4. Image of atomic force microscope 67
Chapter 3 Result 68
3-1. The Effect of Composition on the Packing Density in Liposomes 68
3-1-1. Surface pressure 68
3-1-2. Compression modulus 72
3-2. Interaction Between Peptides and Liposomes 76
3-2-1. Identifying the state of Aβ 76
3-2-2. Leakage measurement for the Aβ in three aggregation states 80
3-3. Amyloid β on Supported Lipid Bilayer 84
3-3-1. Identification of supported lipid bilayer 84
3-3-2. Peptides destroyed the integrity of the supported lipid bilayer 87
3-3-3. Peptide induced pore-like structure formation on the membrane 93
3-4. Identifying the Change of Membrane Thickness with SAXS 97
Chapter 4 Discussion 102
4-1. Molecular Packing of Monolayers with Different Lipid Compositions 102
4-1-1. The effect of varying lipid composition on the molecular packing 102
4-1-2. Compression modulus and membrane compressibility 104
4-2. Various States of Aβ Induce Leakage in the Different Composition 106
4-3. The Effect of Destructive Peptides on Supported Lipid Bilayers 109
4-4. Leakage with Time-Course Measurement in the Different Composition 113
4-5. Changing of Membrane Thickness Induced by Aβ 115
4-6. Difference between Pore and Pore-Like Structure 117
4-7. Mechanism of the Interaction between Aβ and Membrane 118
4-8. Comparison of Aβ and Melittin 119
Chapter 5 Conclusion 120
Reference 122

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指導教授

陳儀帆(Yi-Fan Chen)

審核日期

2017-7-28

推文