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研究生:周姿妤
研究生(外文):Tzu-Yu Chou
論文名稱:研究Cisd2在小鼠阿茲海默症病變過程之神經保護作用
論文名稱(外文):Neuroprotective effect of Cisd2 during pathogenesis of Alzheimer’s diseases in mice
指導教授:蔡亭芬
指導教授(外文):Ting-Fen Tsai
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生命科學系暨基因體科學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:71
中文關鍵詞:阿茲海默症粒線體神經保護作用
外文關鍵詞:Alzheimer’s diseasesmitochondriaCisd2neuroprotective effect
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阿茲海默症 (Alzheimer’s disease, AD)是在老人中最好發的失智症類型,其最主要的發病因子就是年紀的增加。罹患阿茲海默症的病人的腦部會發生病變,導致記憶力和認知能力的逐漸喪失,澱粉樣蛋白(β-amyloid, Aβ)在細胞外的沉積以及神經細胞內的神經纖維糾結(neurofibrillary tangles)是阿茲海默症腦部的病理特色。澱粉樣蛋白前驅蛋白(amyloid precursor protein, APP)以及presenilin 1 蛋白 (PS1)的突變都會導致澱粉樣蛋白的量提高,而且澱粉樣蛋白對於神經細胞是具有高度毒性的。此外,澱粉樣蛋白也會以小分子的形式累積細胞內,造成細胞內胞器功能的下降,例如粒線體功能的傷害。另一種神經退化性疾病,亨丁頓舞蹈症(Huntington's disease, HD)的症狀是不能自主的運動、情緒問題以及逐漸的認知功能下降,造成的原因是第四對染色體內Huntingtin (HTT)基因的CAG三核甘酸重複序列異常擴張,造成突變的Htt蛋白異常累積。突變的Htt蛋白會影響其他蛋白可以被使用的情況,且最主要影響的區域是大腦皮層(cortex)和紋狀體(striatum)部位神經細胞的退化,造成認知能力和運動功能的受損。在阿茲海默症和亨丁頓舞蹈症的病人中大腦都有能量代謝異常的現象,而神經細胞對於能量的需求非常高。CISD2基因是一近期才被研究的新穎基因,對於維持粒線體構造的完整性和功能非常重要。Cisd2蛋白主要位於粒線體外膜上,過去我們證實Cisd2基因剔除小鼠的粒線體結構會破損且伴隨著神經的退化,並且導致小鼠早衰的表現型;另一方面,我們最近也證實過量表現的Cisd2可以延緩自然老化小鼠的神經退化並且延長壽命。因此,在此論文中我們以基因轉殖小鼠為動物模式,想要了解Cisd2的表達量是否會藉由保護神經而影響阿茲海默症和亨丁頓舞蹈症的大腦病變過程,方法是將Cisd2基因轉殖小鼠和阿茲海默症或亨丁頓舞蹈症基因轉殖小鼠進行配種。由腦部切片的病理分析中我們看到Cisd2的過度表達並不影響在阿茲海默症模式小鼠中看到的澱粉樣蛋白的產生,以及之後伴隨的發炎現象。然而,Cisd2的過度表達可以改善因為澱粉樣蛋白毒性以及發炎反應而造成的神經細胞數量下降;此外,電子顯微鏡的結果也顯示Cisd2可以增加阿茲海默症老鼠的神經突觸數量。值得注意地,Cisd2似乎可以改善阿茲海默症模式小鼠的早衰死亡的現象。另一方面,Cisd2的過度表達也可以改善亨丁頓舞蹈症模式小鼠的運動功能喪失。因此,我們的初步實驗結果顯示Cisd2蛋白具有潛在的神經保護作用且可以改善阿茲海默症和亨丁頓舞蹈症小鼠的疾病表現型。
Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and the primary risk factor for AD is age. Affected individuals suffer from graduated brain damage leading to memory loss and cognitive decline. Extracellular β-Amyloid (Aβ) accumulation and intracellular neurofibrillary tangles are hallmarks of the AD brain. Mutations in amyloid precursor protein (APP) and presenilin1 (PS1) had been identified to cause the elevation of aggregation-prone Aβ peptides, which are toxic to neurons. Moreover, accumulation of Aβ in cellular compartment impairs organelle function, including mitochondrial dysfunction. Huntington's disease (HD) is a neurodegenerative disorder that affects muscle coordination and leads to cognitive decline and emotional problems. The causing defect is the expanded CAG repeat in exon 1 of the Huntingtin (HTT) gene. Mutant Htt (mHTT) aggregates interferes the normal availability of proteins. Neuronal degeneration in the striatum and cortex has been shown in HD, which results in impaired motor function and dementia. Disturbance in energy metabolism is also clinical hallmark of AD and HD. Neuronal activities have high demand on energy; therefore, neurons are extremely sensitive to mitochondrial function decline. Cisd2 is a novel gene with a newly identified function involving mitochondria. Previously, we have demonstrated Cisd2, which is a mitochondrial outer membrane protein, is essential for the integrity of mitochondrial structure and functions. In Cisd2 knockout mice, mitochondrial breakdown and dysfunction was observed and followed by neuron degeneration leading to a premature aging phenotype. In contrast, we have demonstrated recently that overexpression of Cisd2 prolongs healthy lifespan and delays aging in Cisd2 transgenic (TG) mice. In this study, we investigate whether overexpression of Cisd2 can affect the brain pathogenesis and ameliorate the disease phenotype in AD and HD mouse models; this were achieved by crossing the Cisd2 TG mice with the AD mouse model (APPswe/PSEN1dE9) and HD model (R6/2). Our histopathological analysis revealed that there were similar levels of Aβ accumulation and inflammation in the hippocampus and cortex of the double TG mice (Cisd2;APPswe/PSEN1dE9) compared with the AD mice. Interestingly, our results showed that overexpression of Cisd2 can prevent neuronal loss in the hippocampus of the double TG mice. In addition, TEM ultra-structure study indicated that Cisd2 seems to protect against mitochondrial degeneration, and mitigate synaptic loss in the hippocampus of the double TG mice. Importantly, the double TG mice appear to have a higher survival rate leading to an extended lifespan. Moreover, impaired motor functions were improved in the double TG mice compared with the HD mice. These results suggest that Cisd2 has a potential neuroprotective effect that can alleviate the disease phenotype in the AD and HD mice.
ABSTRACT
(English)...1
(Chinese)...3

CHAPTER I
Neuroprotective effect of Cisd2 during pathogenesis of Alzheimer’s diseases in mice
Introduction...5
Material and Methods...9
Results
Characterization of Cisd2 transgenic (Cisd2 TG) mice...19
Creation of mice with AD Transgenes in the context of overexpressed Cisd2...20
Overexpressed Cisd2 seems to protect from premature death of AD mice...21
Effect of overexpressed Cisd2 on the Aβ accumulation...21
Neuroinflammation in the brain of AD mice...22
Overexpressed Cisd2 prevents against neuron loss in AD mice...23
Effect of Constitutive overexpression of Cisd2 on autophagy...24
The inducible Pol II-βGeo-Cisd2 transgenic mice...25
Tables &; Figures...26


CHAPTER II
Neuroprotective effect of Cisd2 during pathogenesis of Huntington’s diseases in mice
Introduction...44
Material and Methods...46
Results
Generation of HD mice carrying Cisd2 transgenes...49
Body weight decreased in mice carrying HD transgene...49
Constitutive overexpression of Cisd2 partially improved motor function of HD...50
Survival rate of mice carrying HD transgene...51
Figures &; Appendix...53

CHAPTER III
Discussions...62

REFERENCES...66

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