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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄭尊仁(Tsun-Jen Cheng) | |
dc.contributor.author | Ching-Chou Hsu | en |
dc.contributor.author | 許景洲 | zh_TW |
dc.date.accessioned | 2021-06-15T12:28:13Z | - |
dc.date.available | 2020-08-26 | |
dc.date.copyright | 2020-08-26 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-12 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50032 | - |
dc.description.abstract | 隨著民眾健康意識提升,空氣汙染議題日益受到重視,暴露大氣懸浮微粒(Particulate matter, PM)會對健康產生許多不良效應,過去許多研究已經證實了微粒暴露與心血管、呼吸道疾病之間的致病與機轉。近年來有研究指出,暴露小粒徑的微粒,如細懸浮微粒PM2.5,會影響中樞神經系統(Central nervous system, CNS),造成阿茲海默症(Alzheimer’s disease, AD)等之神經退化性疾病(Neurodegenerative disease)。 AD於病理學上主要有兩大特徵:第一種為由乙型類澱粉蛋白(Beta-amyloid, Aβ)聚集沉積而成的類澱粉蛋白斑塊(Aβ plaque);第二種為Tau蛋白因過度磷酸化而形成的神經纖維纏結(Neurofibrillary tangles, NFTs),這兩種病徵會傷害神經元細胞,造成細胞死亡,最終導致患者認知功能喪失。除此之外,研究指出氧化壓力、微膠細胞活化所導致的發炎反應上調也對神經元細胞死亡有著一定的貢獻。 本研究使用台北空氣汙染暴露系統(Taipei air pollution exposure system, TAPES)進行暴露實驗,TAPES能直接抽取外界大氣中的微粒,輸入至暴露腔內,提供一非濃縮、符合真實大氣環境之暴露條件。此外,本研究使用6個月大的阿茲海默症三基因轉殖小鼠當作實驗動物,進行為期5個月的慢性全身連續性呼吸暴露,由於此品系小鼠能隨著年齡發展出AD相關的病徵,適合用來探討暴露PM後是否會加速小鼠腦中AD相關病徵之變化。 暴露結束後,對小鼠進行了莫氏水迷津行為試驗(Morris water maze),以檢測其空間學習與記憶能力,並於行為試驗結束後進行犧牲。鼠腦會先進行核磁共振成像(Magnetic Resonance Imaging, MRI),並對大腦各區的體積進行定量。影像定量後,半腦的腦組織會細分為皮質(Cerebral cortex)與海馬迴(Hippocampus),並以西方墨點法(Western blot)測量AD特異性指標Aβ42與p-Tau、活化微膠細胞指標CD11b以及自噬作用指標LC3B的蛋白表現量;剩餘半腦的腦組織則進行石蠟包埋與切片染色,透過蘇木精-伊紅染色(Hematoxylin and eosin stain, H E stain)切片對神經元細胞進行計數,並以免疫組織化學染色(Immunohistochemistry stain, IHC stain)切片對AD特異性指標Aβ42、p-Tau、氧化壓力指標丙二醛(Malondialdehyde, MDA)、細胞凋亡酶Caspase-3以及自噬作用蛋白LC3的陽性細胞比例進行計數。 本研究小鼠暴露之PM2.5平均質量濃度為13.85 µg/m3。莫氏水迷津結果顯示在知識採集階段,兩組在各項參數皆無顯著差異,但在空間探索實驗,暴露組在目標象限平台停留時間顯著低於暴露組(p<0.05),其餘參數皆無顯著差異。神經影像學MRI分析結果顯示,兩組小鼠大腦各腦區之體積皆無顯著差異。阿茲海默症相關指標蛋白質定量分析結果顯示,暴露組大腦皮質有四項指標高於控制組(Aβ42 oligomer、 p-Tau、CD11b、LC3B),其中,Aβ42 oligomer蛋白表現量達到統計上之顯著差異(p<0.05),而海馬迴的各項指標皆無顯著差異。p-Tau蛋白表現量在各腦區皆無顯著差異。切片染色分析結果,H E staining切片顯示暴露組大腦皮質與內嗅皮質的神經元細胞數目顯著低於控制組(p<0.05),海馬迴則無顯著差異。IHC staining切片結果顯示,各項指標於各腦區皆無顯著差異。 我們的研究結果顯示慢性呼吸暴露大氣懸浮微粒會誘導小鼠大腦皮質中阿茲海默症特異性指標Aβ42 oligomer的上升與神經元細胞數目減少,導致小鼠的空間記憶能力下降,提供了微粒暴露加速阿茲海默症相關病徵形成的可能機制。 | zh_TW |
dc.description.abstract | Previous studies have confirmed that particulate matter (PM) exposure can induce cardiovascular and respiratory disease. In recent years, PM2.5 has been implicated in the development of neurodegenerative disorders including Alzheimer's disease (AD). There are two specific markers in AD pathology including plaques formed by beta-amyloid (Aβ) accumulation and neurofibrillary tangles (NFTs) formed by aggregation of phosphorylated tau protein. These two markers can damage neuron cells, causing cell death and cognitive deficit. Moreover, oxidative stress and inflammation induced by activated microglia may contribute to AD pathology. We hypothesized that exposure to PM could accelerate AD-like pathology and cause cognitive deficit. To address this, we exposed 6-month-old female triple-transgenic AD mice (3xTg-AD mice), which can develop AD-like pathology, for 5 months to PM by inhalation. Using Taipei Air Pollution Exposure System (TAPES), the TAPES is designed to directly introduce the ambient particles to the exposure chamber, provide a continuous, real world and non-concentrated particle exposure. After exposure, Morris Water Maze (MWM) was used to assess the spatial learning and memory in mice. Magnetic Resonance Imaging (MRI) was used to quantify the brain volume in mice. The cerebral cortex and hippocampus were collected for analysis. Western blot was used to determine the expression of AD specific markers (Aβ42 and p-Tau protein), the marker of activated microglia (CD11b protein) and the marker of autophagy (LC3B protein). The neuronal cells and IHC-positive cells (Aβ42, p-Tau, CD11b, MDA, LC3 and caspase-3) were counted in brain slices. The average concentration of PM2.5 during the exposure was 13.85 µg/m3. While the control and exposure mice had learning effects in the escape latency, the exposed mice showed a significantly decreased spatial memory in time spent in platform quadrant (p<0.05). Western blot showed that the three markers (Aβ42 oligomer, p-Tau and CD11b) in exposure group were higher than controls in cerebral cortex, especially Aβ42 oligomer (p<0.05). The number of neuronal cells in cerebral cortex and entorhinal cortex were significantly decreased in exposure group (p<0.05). IHC-positive cells were not statistically significant between the control and exposure groups. Our study indicated that exposure to PM by inhalation could accelerate AD-like pathology in 3xTg-AD mice in cerebral and entorhinal cortex, causing neuronal death and spatial memory deficit. The study results also support the previous epidemiological findings on the associations between PM and AD. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T12:28:13Z (GMT). No. of bitstreams: 1 U0001-1108202017073700.pdf: 8405639 bytes, checksum: c604518e80ac52c1abdae06ec5f71414 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 目錄 中文摘要 I Abstract III 第一章 前言與研究目的 1 1.1 前言 1 1.2 研究目的 2 第二章 文獻回顧 3 2.1 懸浮微粒之健康效應 3 2.2 懸浮微粒對中樞系統之影響 4 2.3 阿茲海默症 5 2.3.1 類澱粉樣蛋白假說 6 2.3.2 神經纖維纏結假說 6 2.4 微粒暴露與大腦灰質體積變化 8 2.5 微粒暴露與微膠細胞活化 9 2.6 微粒暴露與脂質過氧化 10 2.7 微粒暴露與神經細胞死亡 11 2.8 阿茲海默症三基因轉殖小鼠 13 第三章 材料與方法 14 3.1 實驗流程與架構 14 3.2 實驗動物 15 3.3 大氣懸浮微粒暴露 16 3.3.1 臺北空氣汙染暴露系統(TAPES) 16 3.3.2 大氣微粒及環境監測 16 3.3.3 微粒成分分析 17 3.4 莫氏水迷津 18 3.5 核磁共振成像 19 3.6 阿茲海默症相關指標之蛋白質分析 20 3.6.1 蛋白質萃取 20 3.6.2 蛋白質定量 20 3.6.3 西方墨點法 21 3.6.4 半定量分析 22 3.7 阿茲海默症相關指標之切片染色分析 23 3.7.1 蘇木精-伊紅染色 23 3.7.2 免疫組織化學染色 23 3.7.3 半定量分析 23 3.8 統計方法 24 第四章 結果 25 4.1 實驗動物體重與死亡率 25 4.2 微粒濃度與成份分析 25 4.2.1 暴露期間之微粒濃度 25 4.2.2 暴露期間之微粒成分分析 26 4.3 莫氏水迷津行為試驗 27 4.4 大腦各腦區之體積 28 4.5 各腦區阿茲海默症相關指標之蛋白質表現量 28 4.5.1 各腦區Aβ42 monomer蛋白表現量 28 4.5.2 各腦區Aβ42 oligomer蛋白表現量 28 4.5.3 各腦區p-Tau蛋白表現量 28 4.5.4 各腦區CD11b蛋白表現量 28 4.5.5 各腦區LC3B蛋白表現量 29 4.6 各腦區神經元細胞計數 30 4.7 各腦區阿茲海默症相關指標之切片染色分析 30 4.7.1 各腦區Aβ42切片染色結果 30 4.7.2 各腦區p-Tau切片染色結果 30 4.7.3 各腦區Caspase-3切片染色結果 30 4.7.4 各腦區LC3切片染色結果 31 4.7.5 各腦區MDA切片染色結果 31 第五章 討論 32 5.1 全身性呼吸暴露 33 5.2 PM2.5濃度及組成成份 34 5.3 微粒對空間認知及記憶能力之影響 35 5.4 微粒對大腦灰質體積之影響 36 5.5 微粒對Aβ42之影響 37 5.6 微粒對磷酸化Tau蛋白之影響 39 5.7 微粒對微膠細胞活化之影響 40 5.8 微粒對神經細胞死亡之影響 41 5.9 微粒對大腦皮質之影響 43 5.10 研究限制以及建議 44 第六章 結論 45 第七章 參考資料 46 表格目錄 表 1、微粒暴露與阿茲海默症基因轉殖小鼠相關病徵之研究 56 表 2、暴露期間(2018.11.26~2019.04.23)PM2.5平均質量濃度(μg/m3) 58 表 3、採樣期間內(2018.11.26~2019.04.03),PM2.5可溶性離子組成 59 表 4、採樣期間內(2018.11.26~2019.04.03),PM2.5總金屬組成 60 表 5、採樣期間內(2018.11.26~2019.04.03),PM2.5水溶性金屬組成 61 表 6、莫氏水迷津知識採集階段 62 表 7、莫氏水迷津知識採集階段之學習效應 62 表 8、莫氏水迷津探索實驗 63 表 9、各腦區之體積定量 64 表 10、各腦區之Aβ1-42 monomer蛋白表現量 64 表 11、各腦區之Aβ1-42 oligomer蛋白表現量 64 表 12、各腦區之p-Tau蛋白表現量 64 表 13、各腦區之CD11b蛋白表現量 65 表 14、各腦區之LC3B蛋白表現量 65 表 15、各腦區神經元細胞計數結果 66 表 16、皮質各區Aβ1-42陽性細胞比例;海馬迴CA1區域Aβ1-42斑塊數量 66 表 17、各腦區p-Tau陽性細胞比例 66 圖片目錄 圖 1、慢性全身性呼吸暴露大氣懸浮微粒對阿茲海默症三基因轉殖小鼠神經毒性之影響研究架構。 67 圖 2、慢性全身性呼吸暴露大氣懸浮微粒對阿茲海默症三基因轉殖小鼠神經毒性之影響研究時間軸。67 圖 3、TAPES結構圖 68 圖 4、MWM實驗設備構造圖 69 圖 5、暴露5個月小鼠體重變化 70 圖 6、採樣期間(2019.11.26~2019.04.23) PM2.5成份分析 71 圖 7、採樣期間(2019.11.26~2019.04.23) PM2.5成份分析 72 圖 8、莫氏水迷津知識採集階段 73 圖 9、莫氏水迷津空間探索實驗 74 圖 10、MRI神經影像學分析 75 圖 11、大腦灰質各區之體積 76 圖 12、大腦灰質各區之體積 77 圖 13、大腦皮質之Aβ1-42 monomer蛋白表現量 78 圖 14、海馬迴之Aβ1-42 monomer蛋白表現量 79 圖 15、大腦皮質之Aβ1-42 oligomer蛋白表現量 80 圖 16、海馬迴之Aβ1-42 oligomer蛋白表現量 81 圖 17、大腦皮質之p-Tau蛋白表現量 82 圖 18、海馬迴之p-Tau蛋白表現量 83 圖 19、大腦皮質之CD11b蛋白表現量 84 圖 20、海馬迴之CD11b蛋白表現量 85 圖 21、大腦皮質之LC3B蛋白表現量 86 圖 22、海馬迴之LC3B蛋白表現量 87 圖 23、小鼠大腦皮質H E staining 88 圖 24、小鼠內嗅皮質H E staining 89 圖 25、小鼠梨狀皮質H E staining 90 圖 26、小鼠海馬迴CA1區域H E staining 91 圖 27、H E satin下,神經元細胞在各腦區之計數數量 92 圖 28、H E satin下,神經元細胞在各腦區之計數數量 93 圖 29、小鼠大腦皮質之細胞內Aβ1-42染色 94 圖 30、小鼠內嗅皮質之細胞內Aβ1-42染色 95 圖 31、小鼠梨狀皮質之細胞內Aβ1-42染色 96 圖 32、小鼠海馬迴CA1/Subiculum區域之Aβ1-42斑塊染色 97 圖 33、IHC satin下,Aβ1-42陽性細胞在各腦區之計數數量 98 圖 34、IHC satin下,Aβ1-42陽性細胞在各腦區之計數數量 99 圖 35、小鼠大腦皮質之p-Tau染色 100 圖 36、小鼠內嗅皮質之p-Tau染色 101 圖 37、小鼠梨狀皮質之p-Tau染色 102 圖 38、小鼠海馬迴CA1區域之p-Tau染色 103 圖 39、IHC satin下,p-Tau陽性細胞在各腦區之計數數量 104 圖 40、IHC satin下,p-Tau陽性細胞在各腦區之計數數量 105 圖 41、小鼠大腦皮質之Caspase-3染色 106 圖 42、小鼠內嗅皮質之Caspase-3染色 107 圖 43、小鼠梨狀皮質之Caspase-3染色 108 圖 44、小鼠海馬迴CA1區域之Caspase-3染色 109 圖 45、小鼠大腦皮質之LC3染色 110 圖 46、小鼠內嗅皮質之LC3染色 111 圖 47、小鼠海馬迴CA1區域之LC3染色 112 圖 48、小鼠大腦皮質之MDA染色 113 圖 49、小鼠內嗅皮質之MDA染色 114 圖 50、小鼠海馬迴CA1區域之MDA染色 115 | |
dc.language.iso | zh-TW | |
dc.title | 慢性暴露大氣懸浮微粒對阿茲海默症三基因轉殖小鼠相關病徵之影響 | zh_TW |
dc.title | Effects of chronic exposure to ambient particles on pathology of Alzheimer’s disease in 3xTg-AD mice. | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳達夫(Ta-Fu Chen),莊校奇(Hsiao-Chi Chuang),林靖愉(Ching-Yu Lin) | |
dc.subject.keyword | 大氣細懸浮微粒,阿茲海默症,空間記憶功能缺陷,神經元細胞死亡,自噬作用, | zh_TW |
dc.subject.keyword | ambient fine particles,Alzheimer’s disease,cognitive deficit,neuron death,autophagy, | en |
dc.relation.page | 115 | |
dc.identifier.doi | 10.6342/NTU202002982 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-08-14 | |
dc.contributor.author-college | 公共衛生學院 | zh_TW |
dc.contributor.author-dept | 環境與職業健康科學研究所 | zh_TW |
顯示於系所單位: | 環境與職業健康科學研究所 |
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