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研究生:陳宇綮
研究生(外文):Yu-Chi Chen
論文名稱:探討由Aβ及其它阿滋海默氏症相關危險因子引發tau磷酸化之影響及其機制
論文名稱(外文):Investigation of the effect and underlying mechanism of Aβ and other risk factors of Alzheimer’s disease mediated tau phosphorylation
指導教授:蕭永基蕭永基引用關係
指導教授(外文):Young-Ji Shiao
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:56
中文關鍵詞:阿滋海默氏症tau 磷酸化
外文關鍵詞:Alzheimer’s diseasetau phosphorylation
相關次數:
  • 被引用被引用:1
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  • 下載下載:106
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阿滋海默氏症(Alzheimer’s disease, AD)是一種神經退化性疾病,為失智症(dementia)中最常見的疾病。其主要病理上特徵為在神經細胞外由Aβ所聚而成的老年斑塊(senile plaques, SPs)及在細胞內有由過度磷酸化的tau所組成神經纖維糾結(neurofibrillary tangles, NTFs)。以往阿滋海默氏症的病因主要被認為是Aβ在腦部組織聚集成為老年斑,所引發神經退化。但目前有許多研究發現,單由Amyloid 並不足以造成阿滋海默氏症中神經喪失及認知衰退的現象。因此,Aβ及tau在引起阿滋海默氏症上皆扮演重要的角色,而其中tau的磷酸化作用可能是Aβ、微小膠細胞、興奮性毒性及氧化壓力所引起。本實驗主要目的為觀察由Aβ、微小膠細胞、興奮性毒性及氧化壓力引發tau過度磷酸化之影響,進一步在研究由Aβ及微小膠細胞所調控tau磷酸化作用之機制。以A��25-35 fibril及A��1-42 oligomer處理分析Ser404磷酸化的情形,有顯著增加的現象,而在Ser413、Ser214及Thr212 的磷酸化則沒有改變;利用大腦皮質神經元與BV2細胞共同培養下,以A��1-42 fibril 及A��1-42 oligomer處理分析Ser404,有顯著增加磷酸化的現象。這些結果顯示Aβ可直接或間接透過微小膠細胞來引發tau的磷酸化作用。在觀察興奮性毒性及氧化壓力對tau磷酸化之影響方面,分別以N-methyl-D-aspartate (NMDA)及H2O2處理大腦皮質神經元,以NMDA處理在Ser404分子量72 kD有顯著磷酸化增加的現象,而在Ser413及Ser214下皆沒有顯著增加磷酸化的情形;但在Thr212上,隨著處理濃度及時間的增加則有明顯抑制磷酸化的現象。另外一方面,以H2O2處理大腦皮質神經元分析Ser404,沒有顯著磷酸化增加的結果。在觀察tau磷酸化機制方面,GSK-3�珙陘@造成tau磷酸化的激酶。以A��1-42 oligomer處理大腦皮質神經元,有顯著降低GSK-3�狺WSer9的磷酸化。而以A��1-42 fibril 及A��1-42 oligomer處理與BV2細胞共同培養的大腦皮質神經元,則無活化GSK 3�猁滷“峞C
Alzheimer’s disease (AD), the most common neurodegenerative dementia, is neuropathologically characterized by the extracellular Amyloid ���n�vA���w�npeptides accumlation forming a senile plaque and the intracellular accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Amyloid plaques were considered as the prime pathogenic driver of neurodegeneration in AD. However, many studies suggested that amyloid plaques alone may not be able to explain the neuron loss and cognitive ability decline in AD. Therefore, both Aβand tau were equally important on AD pathogenesis, and tau phosphorylation may be induced by Aβ, microglia, excitotoxicity and oxidative stress. The aim of this thesis is to investigate the effects of tau hyperphosphorylation mediated by Aβ, microglia, excitotoxicity and oxidative stress. Futhermore, the mechanism of Aβ- and microglia– mediated tau phosphorylation was also investigated. We found that Aβ25-35 fibril and Aβ1-42 oligomer significantly increased tau phosphorylation at Ser404, but not at Ser413, Ser214 and Thr212 in cortical neurons, Aβ1-42 fibril and oligomer significantly increased tau phosphorylation at Ser404 in the co-culture of cortical neuons with microglia-derived cell line (BV2). The results suggest that Aβ may induce neuronal tau phosphorylation directly or indirectly through microglia activation by Aβ. In respect of tau phosphorylation mediated by excitotoxicity and oxidative stress, cortical neurons were treated with N-methyl-D-asparate (NMDA) and H2O2, respectively. NMDA significantly increased tau phosphorylation of 72-kDa band at Ser404, but not at Ser413 and Ser214. Nevertheless, tau phosphorylation Thr212 decreased in a concentration and time dependent manner. On the other hand, H2O2 failed to induce tau phosphoryaltion at Ser404 in cortical neurons. Regarding the mechanism of tau phosphoryaltion, GSK- 3�� is one of the tau-protein kinases. We found that Aβ1-42 oligomer decreased the phosphorylation of GSK-3���nat Ser9 (the inactive from of GSK-3��). On the contrary, the GSK-3�� activation induced by Aβ1-42 oligomer and fibril were not observed in the co-culture of cortical neurons and BV2 cells.
圖表目錄........................ I
縮寫表..........................III
中文摘要.........................V
英文摘要.........................VI
緒論.............................1
目的.............................12
實驗材料.........................13
實驗方法.........................17
實驗結果.........................21
討論.............................25
參考文獻.........................31
圖表.............................41
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