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系統識別號 U0026-1807201613072300
論文名稱(中文) 探討額顳葉神經退化性疾病中神經再生的角色及治療可行性評估
論文名稱(英文) The Role of Neurogenesis in Frontotemporal Lobar Degeneration and its Therapeutic Potential
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 104
學期 2
出版年 105
研究生(中文) 林家瑋
研究生(英文) Chia-Wei Lin
學號 S96034043
學位類別 碩士
語文別 英文
論文頁數 50頁
口試委員 指導教授-蔡坤哲
口試委員-江伯敏
口試委員-王亮超
中文關鍵字 額顳葉神經退化性疾病  神經再生  發炎  褪黑激素  認知功能 
英文關鍵字 FTLD  neurogenesis  inflammation  melatonin  cognitive function 
學科別分類
中文摘要 額顳葉神經退化性疾病(Frontotemporal lobar degeneration)是一漸進性腦部退化的疾病,在所有失智症中排名第二位,其病理上特徵為大腦額顳葉處有神經缺失的情況,臨床上症狀為個性改變、認知功能障礙等。目前研究認為可能與TDP-43蛋白有關,而在過去實驗室所建立的額顳葉神經退化疾病模式小鼠TDP-43基因轉殖鼠中,發現星狀膠質細胞有大量增生(microgliosis)的情況,而這被認為腦部可能有發炎的情形。
在成年人海馬迴(adult hippocampus)當中存在一群具有再生能力的神經幹細胞(neural stem cell, NSC),神經幹細胞分化成為成熟的神經細胞,其過程就稱為神經再生(neurogenesis)。而外在及內在的因子,皆會影響神經再生;有研究指出促進發炎激素(pro-inflammatory cytokine)會抑制神經再生的能力。
近年有大量文獻指出,在神經性退化疾病當中,觀察到神經再生功能有缺失的情況。而神經再生被認為與學習記憶有關。因此本研究想去探討在額顳神經退化性疾病中神經再生缺失的相關機轉,並以其為策略,期望發展出治療可行性。
首先,我們利用螢光免疫染色方式檢視額顳葉退化疾病模式老鼠大腦中神經幹細胞的數量、分裂能力以及分化能力,發現與年紀相同的野生型小鼠相比,額顳葉退化疾病模式老鼠中神經幹細胞的數量、增生以及分化皆有顯著性的減少。下一步,我們進一步利用細胞激素蛋白表達微陣列(cytokine array)檢視腦部發炎的情況,我們發現促發炎因子表現皆有上升的情況,並且Eotaxin1蛋白在額顳葉退化疾病模式老鼠中有最高的表現量,而過去研究已經證明Eotaxin1會抑制神經再生的能力,並影響學習記憶能力。因此,我們想利用抗發炎策略,來調查是否可以改善疾病的症狀,我們使用褪黑激素(Melatonin)是一由腦部松果體所分泌的賀爾蒙,可調節生理時鐘。過去文獻指出褪黑激素可作為過氧化物的清除者,而近期的研究在體外實驗中發現,褪黑激素可以增加神經幹細胞存活及分化能力。實驗結果發現給予褪黑激素能降低Eotaxin1在血清中的表現量及改善額顳葉退化疾病小鼠運動及認知功能;雖然給予褪黑激素不能增加神經幹細胞的數目,但能提升神經幹細胞分化成神經細胞的趨勢。最後,在分子機制探討上,我們發現在神經幹細胞中,褪黑激素能有效減少Eotaxin1的表現,並提升促分化轉錄因子Mash1的表現,促使神經幹細胞分化成神經細胞。
總結,本篇論文發現在額顳葉退化性疾病中由發炎所引起的神經幹細胞再生缺失的情況,並利用褪黑激素抗發炎的能力,成功的改善腦中發炎現象,並且能有效地回復運動及認知功能,提供可能的神經保護的策略。
英文摘要 Frontotemporal lobar degeneration is a form of dementia, which has progressive leads neuronal loss in the temporal and frontal lobes. The characteristics of FTLD include behavioral dysfunction and abnormality of motor function. Moreover, the TDP-43 transgenic mice, a FTLD mouse model, reveal the gliosis at 2 -months of age, suggesting an increased level of inflammation.
Neurogenesis is the process that constitutive generation of neuronal cells from neural stem cells (NSCs). Previous studies had shown that inflammatory cytokines, such as TNF-α and IL-1β, would intefere the neurogenesis.
Recently, growing evidences suggest that adult neurogenesis is dysregulated in neurodegenerative disease. Besides, neurogenesis is involved in formation of new memory. Accordingly, we intend to investigate whether melatonin can ameliorate the inflammation, promote neuronal differentiation of NSC, and provide neuroprotective effects in FTLD-U mouse model.
First, we found that neurogenesis was impaired in FTLD mouse model. Next, we performed cytokine array to further confirm that FTLD mice exhibited higher relative expression level of inflammatory cytokines and chemokines in the brain and the level of eotaxin1 was significant increased comparing to age-match control mice. Based on these observation, we used melatonin, which had been reported to have anti-inflammation effects, to test its protective potential. We gave melatonin for 4 months and found that melatonin could improve behavior deficits in FTLD mouse model. Final, we identified that melatonin could decrease the expression level of eotaxin1 and increase the expression of pro-neural transcription factor, Mash1 in vivo.
Together, we found that melatonin supplement can resolve the inflammation in FTLD mouse model and promote the neurogenesis and improve the cognitive function. This study provide a potential neuroprotective strategy for FTLD.
論文目次 中文摘要……………………………………………………………i
Abstract………………………………………………………………iii
致謝……………………………………………………………………v
Contents……………………………………………………………vii
Background……………………………………………………1
Materials and Methods…………………………………………………15
Results ……………………………………………………………………22
Discussion………………………………………………………………………27
References………………………………………………………………………33
Table and Figure legends ……………………………………………44
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