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系統識別號 U0026-1503201513522000
論文名稱(中文) 跑步機運動保護阿茲海默氏症基因轉殖小鼠之海馬迴及杏仁體避免神經退化
論文名稱(英文) Treadmill exercise protects hippocampus and amygdala from neurodegeneration in Alzheimer’s disease transgenic mice
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 林子韡
研究生(英文) Tzu-Wei Lin
學號 S58991219
學位類別 博士
語文別 英文
論文頁數 84頁
口試委員 指導教授-郭余民
口試委員-任卓穎
口試委員-吳豐森
召集委員-何盧勳
口試委員-薛一蘋
口試委員-許勤
中文關鍵字 阿茲海默氏症  運動  海馬迴  杏仁體  學習與記憶 
英文關鍵字 Alzheimer’s Disease  exercise  hippocampus  amygdala  learning and memory 
學科別分類
中文摘要 阿茲海默氏症(Alzheimer’s disease, AD)是一老化相關的神經退化性疾病。病理檢驗和腦部影像研究都指出,海馬迴和杏仁核的神經退化,早在阿茲海默氏症的初期病患身上,就已經發生。運動訓練已知可以促進海馬迴及杏仁核相關的神經功能。所以,本實驗的目的是研究跑步機運動,對年輕APP/PS1基因轉殖小鼠(阿茲海默氏症實驗模式鼠)海馬迴及杏仁核神經結構及功能的影響。首先,我們分析二到四個月大基因轉殖小鼠的海馬迴及杏仁核的神經功能。基因轉殖小鼠在此年紀還未出現阿茲海默氏症的病理-乙型澱粉樣蛋白堆積。我們發現早在二個月大的基因轉殖小鼠,杏仁核相關的長期記憶表現,就已經比無基因轉殖的對照小鼠差;而基因轉殖小鼠海馬迴相關的長期記憶表現,則到四個月大仍然正常。神經突觸複雜度分析顯示,基因轉殖小鼠的杏仁核底側核神經細胞,從二個月大開始,就已經比無基因轉殖的對照小鼠低;而海馬迴CA1及CA3的神經樹突複雜度,則到四個月大仍與對照小鼠類似。此外,腦源神經生長因子/酪氨酸激酶B受體(BDNF/TrkB)和下游訊息分子 (例如:p-TrkB、p-Akt及p-PKC)的活化程度,在基因轉殖小鼠杏仁核下降的時間早於在海馬迴下降的時間。十周的跑步機訓練(從1.5個月大至4個月大),不但增加基因轉殖小鼠海馬迴相關的學習記憶表現及CA1和CA3神經樹突的複雜度,也恢復杏仁核相關學習記憶的表現及杏仁核底側核神經的突觸複雜度。同時,運動訓練也增加p-TrkB、p-Akt及p-PKC在海馬迴及杏仁核的表現。我們還發現,運動訓練降低乙型澱粉樣蛋白在海馬迴及杏仁核的濃度。運動訓練並沒有改變乙型澱粉樣蛋白前體蛋白(amyloid precursor protein)或糖基化終產物受體(receptor for advanced glycation end-product)的表現量,但明顯的增加低密度脂蛋白受體相關蛋白(low-density lipoprotein-related protein-1)在基因轉殖小鼠兩個腦區的濃度。總結以上,我的結果支持杏仁核的神經退化比海馬迴早發生。長期的運動訓練可保護海馬迴及杏仁核神經,抵抗阿茲海默氏症相關的退化,可能的機制包括有促進腦源神經生長因子訊息路徑及增加乙型澱粉樣蛋白的清除。據此,我們建議運動可被視為一個有效延緩阿茲海默氏症發生的策略。
英文摘要 Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Results from post-mortem examination and brain imaging studies reveal that neurodegeneration has already occurred in both the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Therefore, the objective of this study is to investigate the effect of treadmill exercise on the structure and function of neurons in the hippocampus and amygdala of young (2, 3 and 4 months of age) APP/PS1 double transgenic (Tg) mice, a widely used AD mouse model. These ages are younger than the typical onset time of amyloid deposition (6-months-old). Compared to wild-type littermates (Wt ), Tg mice performed worse in amygdala-dominant memory at all three ages, while hippocampus-dominant memory remained intact until 4-month-old. The dendritic arbors of neurons in the basolateral amygdala were reduced in Tg mice as early as 2-months-old, while the dendritic arbors of neurons in the hippocampal CA1 and CA3 regions were relatively intact. The levels of BDNF-TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala earlier than in the hippocampus of the Tg mice. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-Akt and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Aβ in the hippocampus and amygdala. Exercise training did not change the levels of amyloid precursor protein or receptor for advanced glycation end-product, but significantly increased the levels of low-density lipoprotein-related protein-1 in both brain regions of the Tg mice. Taken together, these results suggest that neurodegeneration occurs earlier in the amygdala than in the hippocampus. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Aβ clearance. Therefore, we suggest that running exercise may serve as a means to delay the onset of AD.
論文目次 Abstract in Chinese 2
Abstract in English 4
Acknowledge 6
List of Figures 9
Abbreviations 11
Introduction 12
Hypothesis and Experiment Design 17
Materials and Methods 19
Results 28
Discussion 38
References 47
Figures and Legends 67
Curriculum Vitae 83
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