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題名 新型抗發炎硫脲小分子藥物能改善微膠質細胞因β-澱粉樣蛋白所引起之粒線體功能缺失
A novel thiourea possessing anti-inflammatory property rescues Aβ-induced mitochondrial dysfunction in microglia
作者 孫儀馨
Sun, Yi-Sin
貢獻者 詹銘煥
孫儀馨
Sun, Yi-Sin
關鍵詞 阿茲海默氏症
微膠質細胞
β-澱粉樣蛋白
粒線體
生物能量
硫脲
Alzheimer’s disease
Microglia
Beta-amyloid
Mitochondria
Bioenergetics
Thiourea
日期 2018
上傳時間 1-Oct-2018 12:12:04 (UTC+8)
摘要 阿茲海默氏症 (Alzheimer’s disease) 是一種常見的神經退化性疾病，其特徵為大腦中神經細胞漸進性的損傷以及微膠質細胞的過度活化。除此之外，β-澱粉樣蛋白 (Aβ) 的堆積是阿茲海默氏症中重要的病理特徵，並在疾病的發展中扮演重要的角色。由於β-澱粉樣蛋白的製造與清除失衡，使得β-澱粉樣蛋白產生堆積。而過多的β-澱粉樣蛋白會過度活化微膠質細胞，也會引發神經細胞之粒線體功能缺陷。病理過程造成慢性神經性發言及神經性退化的後果，最終導致神經元死亡。然而，β-澱粉樣蛋白對於微膠質細胞之粒線體的影響以及相關機制，卻較少被探討。因此，我們假設β-澱粉樣蛋白會引起微膠質細胞中粒線體功能的損傷，並間接影響微膠質細胞所調控的免疫發炎反應。本研究將微膠質細胞暴露在β-澱粉樣蛋白下，並檢測其粒線體的功能，包含生物能量（bioenergetics）、粒線體形態，以及相關訊號傳遞路徑的變化。此外，一個新型硫脲小分子藥物＃326，由於具有抗發炎能力，因此本篇研究進一步測試＃326是否能透過抗發炎的反應，來挽救受到β-澱粉樣蛋白所導致的粒線體功能缺失。本篇研究結果顯示，β-澱粉樣蛋白會降低粒線體的生物能量及改變粒線體形態與分佈，造成微膠質細胞中粒線體的功能損害。此外，β-澱粉樣蛋白會促進微膠質細胞中ERK的磷酸化。然而，在β-澱粉樣蛋白的作用下，#326不僅能挽救粒線體的功能缺失，並能降低β-澱粉樣蛋白引發之ERK過度磷酸化。據此推斷，#326可能透過調解ERK的訊號傳遞路徑，改善β-澱粉樣蛋白引起的線粒體失能。總結以上，我們的研究結果顯示#326能改善β-澱粉樣蛋白對微膠質細胞中線粒體功能的損害，而這種粒線體保護功能，可能與其調解ERK1/2的過度磷酸化作用有關。此外，透過研究新型的硫脲小分子藥物#326的作用機制，或許能得到阿茲海默氏症病理研究的相關線索，甚至對神經退化性疾病的藥物治療發展中有所幫助。
Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the progressive neuronal loss and overactive microglia. Besides, amyloid-β (Aβ) is a histopathological hallmark in AD, which plays a crucial role in the pathogenesis of this disease. The imbalance between Aβ production and clearance leads to the accumulation of Aβ in extracellular and intracellular compartments. Growing evidence suggests that excessive amyloid-β (Aβ) accumulation instigates early deficits in mitochondrial function and causes a self-propelling degeneration cycle which sustains chronic neuroinflammation induced by microglial and eventually lead to neuronal damages. Nevertheless, how Aβ affects mitochondrial function in microglia is still elusive. In this study, it was hypothesized that Aβ would cause mitochondrial defects in microglia and further exacerbate microglial activation which is the causation of neuronal inflammation in AD.
To investigate this premise, mitochondrial function, including mitochondrial bioenergetics, mitochondrial morphology, and mitochondrial relative pathway were tested in microglial cells challenged with Aβ. In addition, the protective effects of a novel thiourea, compound #326, which possesses anti-inflammatory effect were also been examined in this study. Our data indicated that Aβ impaired mitochondrial function as evidenced by the decreased bioenergetics, fragmented mitochondria, and abnormal distribution. In addition, our results also showed the activation of extracellular-signal regulated kinase (ERK) phosphorylation under Aβ stimulation. Intriguingly, our data indicated that the rescuing effects of the novel compound on the aberrant bioenergetics elicited by Aβ are involved in the modulation of ERK activity that is highly associated with mitochondrial damages under the circumstances of Aβ toxicity. Therefore, studying the mechanism of the new thiourea, compound #326, may provide the clues to study the pathology of AD, and even improve the design of pharmacological intervention for AD.
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描述 碩士
國立政治大學
神經科學研究所
105754007
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0105754007
資料類型 thesis
dc.contributor.advisor 詹銘煥zh_TW
dc.contributor.author (Authors) 孫儀馨zh_TW
dc.contributor.author (Authors) Sun, Yi-Sinen_US
dc.creator (作者) 孫儀馨zh_TW
dc.creator (作者) Sun, Yi-Sinen_US
dc.date (日期) 2018en_US
dc.date.accessioned 1-Oct-2018 12:12:04 (UTC+8)-
dc.date.available 1-Oct-2018 12:12:04 (UTC+8)-
dc.date.issued (上傳時間) 1-Oct-2018 12:12:04 (UTC+8)-
dc.identifier (Other Identifiers) G0105754007en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/120265-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 105754007zh_TW
dc.description.abstract (摘要) 阿茲海默氏症 (Alzheimer’s disease) 是一種常見的神經退化性疾病，其特徵為大腦中神經細胞漸進性的損傷以及微膠質細胞的過度活化。除此之外，β-澱粉樣蛋白 (Aβ) 的堆積是阿茲海默氏症中重要的病理特徵，並在疾病的發展中扮演重要的角色。由於β-澱粉樣蛋白的製造與清除失衡，使得β-澱粉樣蛋白產生堆積。而過多的β-澱粉樣蛋白會過度活化微膠質細胞，也會引發神經細胞之粒線體功能缺陷。病理過程造成慢性神經性發言及神經性退化的後果，最終導致神經元死亡。然而，β-澱粉樣蛋白對於微膠質細胞之粒線體的影響以及相關機制，卻較少被探討。因此，我們假設β-澱粉樣蛋白會引起微膠質細胞中粒線體功能的損傷，並間接影響微膠質細胞所調控的免疫發炎反應。本研究將微膠質細胞暴露在β-澱粉樣蛋白下，並檢測其粒線體的功能，包含生物能量（bioenergetics）、粒線體形態，以及相關訊號傳遞路徑的變化。此外，一個新型硫脲小分子藥物＃326，由於具有抗發炎能力，因此本篇研究進一步測試＃326是否能透過抗發炎的反應，來挽救受到β-澱粉樣蛋白所導致的粒線體功能缺失。本篇研究結果顯示，β-澱粉樣蛋白會降低粒線體的生物能量及改變粒線體形態與分佈，造成微膠質細胞中粒線體的功能損害。此外，β-澱粉樣蛋白會促進微膠質細胞中ERK的磷酸化。然而，在β-澱粉樣蛋白的作用下，#326不僅能挽救粒線體的功能缺失，並能降低β-澱粉樣蛋白引發之ERK過度磷酸化。據此推斷，#326可能透過調解ERK的訊號傳遞路徑，改善β-澱粉樣蛋白引起的線粒體失能。總結以上，我們的研究結果顯示#326能改善β-澱粉樣蛋白對微膠質細胞中線粒體功能的損害，而這種粒線體保護功能，可能與其調解ERK1/2的過度磷酸化作用有關。此外，透過研究新型的硫脲小分子藥物#326的作用機制，或許能得到阿茲海默氏症病理研究的相關線索，甚至對神經退化性疾病的藥物治療發展中有所幫助。zh_TW
dc.description.abstract (摘要) Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the progressive neuronal loss and overactive microglia. Besides, amyloid-β (Aβ) is a histopathological hallmark in AD, which plays a crucial role in the pathogenesis of this disease. The imbalance between Aβ production and clearance leads to the accumulation of Aβ in extracellular and intracellular compartments. Growing evidence suggests that excessive amyloid-β (Aβ) accumulation instigates early deficits in mitochondrial function and causes a self-propelling degeneration cycle which sustains chronic neuroinflammation induced by microglial and eventually lead to neuronal damages. Nevertheless, how Aβ affects mitochondrial function in microglia is still elusive. In this study, it was hypothesized that Aβ would cause mitochondrial defects in microglia and further exacerbate microglial activation which is the causation of neuronal inflammation in AD.
To investigate this premise, mitochondrial function, including mitochondrial bioenergetics, mitochondrial morphology, and mitochondrial relative pathway were tested in microglial cells challenged with Aβ. In addition, the protective effects of a novel thiourea, compound #326, which possesses anti-inflammatory effect were also been examined in this study. Our data indicated that Aβ impaired mitochondrial function as evidenced by the decreased bioenergetics, fragmented mitochondria, and abnormal distribution. In addition, our results also showed the activation of extracellular-signal regulated kinase (ERK) phosphorylation under Aβ stimulation. Intriguingly, our data indicated that the rescuing effects of the novel compound on the aberrant bioenergetics elicited by Aβ are involved in the modulation of ERK activity that is highly associated with mitochondrial damages under the circumstances of Aβ toxicity. Therefore, studying the mechanism of the new thiourea, compound #326, may provide the clues to study the pathology of AD, and even improve the design of pharmacological intervention for AD.		en_US
dc.description.tableofcontents Approval page I
Acknowledgements II
Abstract III
The list of Tables IX
The list of Figures IX
The list of Abbreviations X
Chapter 1. Introduction XI
1.1 Alzheimer’s disease 1
1.2 Amyloid β 2
1.3 Mitochondrial dysfunction caused by Aβ 3
1.4 Mitochondrial defects in AD 4
1.5 Mitochondrial defects in microglia during the pathogenesis of AD. 5
1.6 Mitochondrial bioenergetics in AD 8
1.7 Morphological changes in mitochondria 9
1.8 Inflammation and mitochondrial dysfunction 9
1.9 BKCa channel 10
1.10 Hypothesis 11
1.11 The approaches and the findings 11
Chapter 2. Materials and Methods 13
2.1 Cell culture 13
2.1.1 SM826 microglial cell culture 13
2.1.2 Primary microglial cell culture 13
2.2 Aβ oligomerization and treatment 14
2.3 Compound #326 preparation 14
2.4 Real time quantitative reverse transcription PCR 15
2.5 Western blot assay 15
2.5.1 Total protein extraction 16
2.5.2 Protein measurement - PierceTM BCA Protein Assay 16
2.5.3 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 16
2.5.4 Western blot imaging 17
2.6 Live cell staining for mitochondrial morphology 18
2.7 Immunoflourescence microscopy and high resolution confocal imaging 18
2.8 Skeletonized images of mitochondria 19
2.9 Mitochondrial bioenergetic measurements 19
2.10 Statistical analysis 20
Chapter 3. Results 21
3.1 Aβ-induced mitochondrial bioenergetic dysfunction in microglial cells 21
3.2 Aβ-induced mitochondrial morphological changes in primary microglial cells 22
3.3 The effect of Aβ on the expression of genes related to mitochondrial morphology 23
3.4 The possible connection between mitochondrial morphology and inflammation 24
Chapter 4. Discussion 26
Tables 31
Figures 32
Reference 46		zh_TW
dc.format.extent 6125109 bytes-
dc.format.mimetype application/pdf-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0105754007en_US
dc.subject (關鍵詞) 阿茲海默氏症zh_TW
dc.subject (關鍵詞) 微膠質細胞zh_TW
dc.subject (關鍵詞) β-澱粉樣蛋白zh_TW
dc.subject (關鍵詞) 粒線體zh_TW
dc.subject (關鍵詞) 生物能量zh_TW
dc.subject (關鍵詞) 硫脲zh_TW
dc.subject (關鍵詞) Alzheimer’s diseaseen_US
dc.subject (關鍵詞) Microgliaen_US
dc.subject (關鍵詞) Beta-amyloiden_US
dc.subject (關鍵詞) Mitochondriaen_US
dc.subject (關鍵詞) Bioenergeticsen_US
dc.subject (關鍵詞) Thioureaen_US
dc.title (題名) 新型抗發炎硫脲小分子藥物能改善微膠質細胞因β-澱粉樣蛋白所引起之粒線體功能缺失zh_TW
dc.title (題名) A novel thiourea possessing anti-inflammatory property rescues Aβ-induced mitochondrial dysfunction in microgliaen_US
dc.type (資料類型) thesisen_US
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dc.identifier.doi (DOI) 10.6814/THE.NCCU.IN.006.2018.C05en_US