臺灣博碩士論文加值系統

大量證據表明，氧化壓力是阿滋海默氏病（AD）病理的一啟動因子；清除活性氧化物（ROS），可以有效的預防阿滋海默氏病（AD）病情發展，而含高抗氧化劑的飲食中，提供降低相關風險的潛能。
蝦紅素是來自於甲殼類動物和紅麴所新發現的類葫蘿蔔素保健食品，它具有強力的抗氧化，防光、解肝毒和抗發炎活性。而有關於其抗阿滋海默氏病和神經保護效果的文獻仍較缺乏，我們以Aβ25-35傷害PC12的細胞模式來研究評估其神經保護效果。結果顯示，蝦紅素保護Aβ25-35所引起的傷害是經由下列途經；如防止Aβ25-35寡聚體的直接致命性傷害，穩定胞內鈣平衡，抑制了活性氧產生，降低caspase-3/procaspase-3之比例，降低了細胞核轉錄因子NFκB活性，細胞激素TNFα/IL-Iβ產生，p38蛋白質磷酸化。確實的，蝦紅素是具有潛力的神經保護劑和抗阿滋海默氏症的輔助治療價值。
分子物理生化的評估指出，金屬離子結合至Aβ澱粉樣蛋白會誘導出過氧化氫（H2O2）產生，過氧化氫會誘發鈣離子從胞外至胞內區間的重新分佈，並導致瞬間膜電位差至少下降208.06毫伏特。以Mark和Houwin經驗方程式，預測出Aβ在腦部產生192小時後，擴散距離在3.96x10-4cm半經範圍內；其最大可溶的型態是12mer，最大擴散係數及最大固有黏度分別為8.24x10-15cm2s-1及87.24 cps。

Substantial evidence has indicated that oxidative stress can be a causative factor in the pathogenesis of Alzheimer''s diseases (AD) and that scavenge ROS level may usefully prevent the development or progress of AD, and that diets high in antioxidants offer the potential to lower the associated risks. Astaxanthine (ASTx) is a novel carotenoid nutraceutics obtained from the crustaceans and red yeasts, having potent antioxidant, photoprotectant, hepatodetoxicant and anti-inflammatory activities. Document concerning the anti-Alzheimer’s disease (anti-AD) and neuroprotective effect of ASTx is still lacking. We utilized the Abeta25-35-PC12 cell model to investigate its neuron protective effect. Results indicated that ASTx protected the damaging effects induced by Abeta25-35 through several pathways, i.e. by blocking the direct fatal effect of Abeta25-35 oligomers, stabilizing calcium homeostasis, suppressing ROS generation, dowregulating the ratio of caspase 3/procaspase 3, downregulating the cytokine pathway, TNFalfa/IL-1beta, increasing translocation of NFkB and taking the pathway through p-p38MAPK. Conclusively, ASTx has a merit to be used as a very potential neuron protective and anti-AD adjuvant therapy.
Molecular physicobiochemical calculations indicated that the metallic ion binding to beta-amyloids (Abeta) may induce production of hydrogen peroxide, which triggers the Ca ion redistribution from the extracellular to the intracellular compartmentation, resulting in a transient membrane electropotential drop by at least 208.06mV. Moreover, using the Mark and Houwink empirical equation, we predicted the diffusible distances of all Abeta identities would be confined in a very tiny region within a radius less than 3.96*10-4cm in brain at 192 h after produced. Because of the inherent tendency of aggregation behaved by the Abeta, the maximum diffusion coefficient and inherent viscosity were 8.24*10-15 cm2s-1 and 87.24 cps for the 12 mers, the largest soluble form of Abeta.

中文摘要 IV
Abstract V
List of Abbreviations VII
List of Figures VIII
List of Tables X
1 Introduction 1
1.1 Pathological Hallmarks of Alzheimer''s Disease 1
1.2 The Amyloid Hypothesis 4
1.3 The Cytotoxicity of Beta-Amyloid 6
1.3.1 Amyloid-Beta Peptides 6
1.3.2 Metallic Ion -Induced Aggregation of Beta-Amyloid 9
1.3.3 Redox Activity of Beta-Amyloid 12
1.3.4 Toxic Action Mechanism of Beta-Amyloid 13
1.4 The risk factors of Alzheimer’s disease 15
1.5 Strategies To Reduce Risks Progressing To Alzheimer’s Disease 16
1.5.1. Risk reduction and Treatment 16
1.5.2 Perspective 19
2 Present investigation 22
2.1 Research Motivation 22
2.2 Materials and Methods 22
2.2.1 Chemicals and Reagents 22
2.2.2 Cell Culture 23
2.2.3 Toxicity Test of Beta-Amyloid 25-35 23
2.2.4 Toxicity Test of Astaxanthine 24
2.2.5 Effect of Astaxanthine Against the Beta-Amyloid25-35 Damaging Effect 24
2.2.6 Assay for Intracellular Reactive Oxygen Species (ROS) Formation 25
2.2.7 Determination of Intracellular Calcium Ions [Ca2+]i 25
2.2.8 Analysis of Released TNF-α and IL-1beta 26
2.2.9 Western Blot and Analysis for Nnuclear Protein Extract 26
2.2.10 Statistical Analysis 30
2.3 Mathematical Modeling 31
2.3.1 Predictive Shock Membrane Potential Changes 31
2.3.2 The diffusible distance of Beta-Amyloids in brain 32
2.3.2.1 The Viscosity Equation for Beta-Amyloids 32
2.3.2.2 Searching For Value of alfa 32
2.3.2.3 Solving For Values of k 33
2.3.3 Predicted Diffusion Rates of Beta-Amyloids 34
2.3.4 Reference Compound for Diffusivity Computation 35
3 Results 36
3.1 Effect of Beta-Amyloid25-35 on PC12 Cells 36
3.2 Effect of Astaxanthine (ASTx) on PC12 cells 36
3.3 Effect of Astaxanthine Against the Damages in PC12 Cells Caused by Beta-Amyloid25-35 36
3.4 Effect ofAstaxanthine on Expression of IL-1beta and TNF-alfa 37
3.5 Effect of astaxanthine on translocation of p65 induced by Beta-Amyloid25-35 37
3.6 Effect of Astaxanthine on Expression of Caspase 3/Pro-Caspase 3 Induced by Beta-Amyloid25-35 37
3.7 Effect of Astaxanthine on Upregulation of p38 MAP kinase (p-p38) Induced by Beta-Amyloid25-35 38
3.8 Effect of Astaxanthine to Suppress the Calcium Influx in PC12 Cells 38
3.9 Effect of Astaxanthine Against the ROS Induced by Beta-Amyloid25-35 38
3.10 Effect of Astaxanthine on Expression of [Bax/Bcl-2] Induced by Beta-Amyloid25-35 39
4 Discussion 40
4.1 Protective Effect of Astaxanthine 40
4.2 mathematical modeling 49
4.2.1 Homeostatic Nernst Membrane Potentials Can be Terribly Perturbed By Beta-Amyloids 49
4.2.2 Toxic Beta-Amyloid Entities Have High Viscosity Approximately Within Range of 39-87 cps 52
5 Concluding remarks 58
5.1 Protective Effect of Astaxanthine 58
5.2 mathematical modeling 59
6.Figures and Tables 60
7.Reference 86

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