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系統識別號 U0026-0812200911101098
論文名稱(中文) 貝它糊蛋白的聚集與神經毒性之探討
論文名稱(英文) beta-amyloid peptide aggregation amd neurotoxicity
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 92
學期 2
出版年 93
研究生(中文) 羅雪琴
研究生(英文) Shiue-Chin Lo
電子信箱 lion6703@yahoo.com.tw
學號 T9690102
學位類別 碩士
語文別 中文
論文頁數 103頁
口試委員 口試委員-楊延光
指導教授-郭余民
召集委員-游一龍
中文關鍵字 神經毒性  貝它糊蛋白 
英文關鍵字 neurotoxicity  beta-amyloid peptide 
學科別分類
中文摘要 中文摘要
  阿茲海默氏症患者腦內所呈現的主要病理特徵為神經細胞外出現大量的老年斑塊以及神經細胞內有纖維化糾結。已有許多研究證實,老年斑塊的周圍出現大量被活化的微小膠細胞及星型膠細胞。老年斑塊的主要組成成分是由一段40或42個胺基酸序列所組成的貝它糊蛋白。貝它糊蛋白可以直接對神經細胞造成神經毒性,亦可間接經由活化的微小膠細胞作用於神經元而引發神經毒性。有研究指出,被活化的微小膠細胞可能參與阿茲海默氏症腦中貝它糊蛋白的形成及神經損傷與死亡。因此,本實驗第一個目的是評估由貝它糊蛋白所活化的微小膠細胞,THP-1細胞,所引發之神經毒性效力。以人類神經纖維瘤母細胞,SH-SY5Y細胞,作為監測微小膠細胞引發神經毒素的模式。我們的實驗結果顯示,貝它糊蛋白主要可直接引起SH-SY5Y細胞死亡,且其毒性與劑量成正相關。半致死劑量約為0.4 �M。而THP-1細胞以相同情況處理後,卻未呈現細胞死亡現象。若以0.2�M的貝它糊蛋白於不同時間點加入THP-1細胞,再取其條件培養液加入SH-SY5Y細胞培養24小時,會造成神經細胞死亡的現象。未經處理過的THP-1細胞的條件培養液,則不會對其造成神經毒性。為了避免培養基中所添加的胎牛血清可能會含有其他干擾神經毒性的因子,因此,接下來的實驗將以不含有胎牛血清的培養基取代。於不含有胎牛血清的培養基狀態下,貝它糊蛋白仍可直接引起SH-SY5Y細胞死亡,且呈現劑量從屬的方式。半致死劑量從之前的0.4 �M減低為0.15 �M。相似情況處理THP-1細胞並不會對其造成毒性。以不同濃度的貝它糊蛋白處理THP-1細胞15分鐘後,再取其條件培養液處理SH-SY5Y細胞培養24小時後發現,SH-SY5Y細胞的存活率隨著貝它糊蛋白加入THP-1細胞的濃度增加而減低。所以,我們的實驗結果顯示,貝它糊蛋白處理之微小膠細胞可釋放出神經毒素,並對神經細胞造成損傷。近年來,有文獻發現水溶性寡聚合體及原纖維絲形式的貝它糊蛋白之聚集,可引起與纖維化糊蛋白類似之神經毒性。因此,我們第二個實驗目的即是確立寡聚合體形式的水溶性貝它糊蛋白具有神經毒性。藉由不同孔徑的薄膜分子篩以離心過濾方式,可將貝它糊蛋白分成不同大小分子量的數個等分。再分別以SH-SY5Y及THP-1細胞來測試不同大小分子量貝它糊蛋白直接與間接的神經毒性。我的實驗結果顯示,以大於30 kDa大小的水溶性寡聚合體貝它糊蛋白具有最高神經毒性。

英文摘要 Abstract

  The pathological hallmarks of Alzheimer’s disease (AD) are the deposition of neuritic plaques extracellularly and accumulation of neurofibrillary tangles intracellularly in the patient’s brain. Extensive studies have demonstrated that neuritic plaques are usually surrounded by activated microglia and astrocytes. The major component of neuritic plaques is the 40 to 42 amino acid long �-amyloid peptide (A�). The abnormal Aβ aggregations in brain could induce various pathologies, such as dystrophic neuritis, synaptic losses, and retraction of the neuritic arbor strongly, which all suggest a pivotal role of Aβ in the AD pathogenesis. Furthermore, A� may exert indirect neuron toxicity through the activation of microglia. Some studies suggest that activated microglia cells might be the link between A� deposition and neuronal degeneration. Therefore, the first objective of this study was to evaluate Aβ peptide-induced neuronal toxicity in microglia-like THP-1 cells. Human neuroblastoma cells, SH-SY5Y, were used to monitor the neurotoxicity of THP-1 secreted neurotoxins. Our results showed that A� was capable of inducing SH-SY5Y cell death in a dose-dependent manner with a LD50 = 0.4�M of A�, whereas the THP-1 cells were spared. When the THP-1 cells were treated with 200nM of Aβ, the THP-1 condition media (CM) demonstrated neurotoxicity with a maximal effect at 3h. To avoid the confounding effects in serum, the culture medium was switched from the serum-containing medium to serum-free medium. In the serum-free culture condition, A� induced SH-SY5Y cell death in a dose-dependent manner (LD50 = 0.15�M). Such effects were not observed in THP-1 cells. THP-1 cells were then treated with different concentrations of A� for 15 min and the THP-1 CM was transferred to SH-SY5Y cells for 24h. I found that the viabilities of SH-SY5Y cells decreased as the THP-1 cell treated Aβ concentrations increased. These results suggested that microglia can release neurotixins upon the stimulation by Aβ oligomers and prefibrillar aggregated were the proximal effectors of neurotoxicity. The second objective of my study was to identify the A� oligomer species that responsible for its neurotoxicity. A� peptides were separated into different molecular weight fractions using graded membrane filtration and the toxicity of each fraction was examined. My results showed that soluble form of A� ranging over 30 kDa was the major A� species causing the toxicity.

論文目次 目錄
頁數
表目錄 i
圖目錄 ii
中文摘要 1
英文摘要 3
緒論 5
實驗目的與策略 19
方法 23
實驗結果 42
參考文獻 62
自述 96
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