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研究生:陳嘉萍
研究生(外文):Chia-ping Chen
論文名稱:探討微小膠細胞對beta-amyloid神經元毒性之影響及其作用機制
論文名稱(外文):Investigation of the effect and underlying mechanism of microglia on beta-amyloid protein mediated neurotoxicity
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:2004
畢業學年度:92
語文別:中文
論文頁數:71
中文關鍵詞:微小膠細胞乙型澱粉樣生肽
外文關鍵詞:microgliabeta-amyloid
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在罹患阿滋海默氏症的病患大腦皮質層以及海馬迴中發現神經元內有神經纖維纏結,而神經元外有大量老人斑的堆積,老人斑主要由類澱粉纖絲(amyloid fibril)所組成,周圍則有活化的微小膠細胞散布。因此A□與微小膠細胞在阿滋海默氏的致病過程中扮演著重要的角色,但究竟是A□的存在活化了微小膠細胞而造成神經細胞的毒殺抑或□□直接造成神經元細胞的毒殺而活化了微小膠細胞,迄今仍未有一定論。因此本研究在於探討A□、神經元細胞與微小膠細胞三者間的交互作用,期望能夠釐清三者之間的因果關係。本實驗依據特定的條件培養出A與B兩型微小膠細胞,在形態上A型細胞類似微小膠細胞的progenitor而B型細胞則較像休息狀態之微小膠細胞。兩型細胞皆表現巨噬細胞標記蛋白:cluster of differentiation 11b (CD11b) 和CD68,而不表現CD11c、macrophage inflammatory protein-1□ (MIP-1□)、interleukin-1□ (IL-1□)、tumor necrosis factor-□ (TNF-□)、和inducible nitric oxide synthase (iNOS)。兩型細胞對LPS的反應有多項差異,包括:1) LPS誘導B型而非A型細胞表現CD11c和MIP-1□,2) LPS增加B型細胞的CD68,而減少A型細胞的CD68,3) LPS明顯的增加B型細胞釋出IL-1□、TNF-□、和nitiric oxide,在A型細胞則程度較小,4) LPS誘導A型而非B型細胞增生。雖然interferon-□ (IFN-□)對兩型細胞的增生都有誘導作用, 然而對nitiric oxide的產生卻有差異性的影響。IFN-□只誘導B型細胞產生nitiric oxide,但是它的確增加LPS刺激A型細胞產生nitiric oxide的量。接著我們進一步探討兩型細胞受三種A□□□A□25-35、A□1-42 oligomer、和A□1-42 fibril)或A□刺激過神經元的調整培養液(conditioned medium of A□-stimulated neuron,CMAN)的作用。只有A□25-35誘導A型細胞表現MIP-1□,三種A□皆誘導B型細胞釋出TNF-□,但是只有A□25-35誘導兩型細胞釋出IL-1□。A□25-35-CMAN對B型細胞的毒性比直接加入A□的小。微小膠細胞與神經元的近距離共同培養,其A□23-35的神經元毒性明顯地被A型而非B型細胞所抑制。A□刺激過微小膠細胞的調整培養液被用來闡述A□、微小膠細胞、與神經元三者的作用。結果證明A型細胞處理高濃度的A□25-35或是B型細胞處理A□1-42 fibril所得的調整培養液皆比直接加入A□表現更強的毒性。所以兩型微小膠細胞受不同衝擊在許多方面會表現專一的特性,如chemoattractive factor的表現、發炎性細胞激素的釋出、和神經元毒性。而這些作用可能參與阿滋海默氏症的治病機制。
There are two pathological hallmarks in the patients of Alzheimer’s disease (AD), including extracellular senile plaque and intracellular neurofibrillary tangels in the cortex and hippocampus. Senile plaque is composed of amyloid fibril and surrounded by activated microglial cells. Therefore, both amyloid beta-peptide (A□) and microglia are pivotal in the pathogensis of AD. Nevertheless, it is still unclear that A□-mediated activation of microgla causes the neuronal toxicity or the activation of microglia is only the consequence of neural death induced by A□. In the present study we attempt to delineate the interaction between A□, neurons, and microglial cells. The results will address the cause-consequence relationship between these three items. Two types of microglia, type A and B, had been identified by specific culture condition in the present study. Type A and type B microglia were morphologically similar to microglial progenitor and resting microglia, respectively. Two types of microglia expressed the microphage marker cluster of differentiation 11b (CD11b) and CD68, whereas they did not contain CD11c, microphage inflammatory protein-1□ (MIP-1□), interleukin-1□ (IL-1□), tumor necrosis factor-□ (TNF-□), and inducible nitric oxide synthase (iNOS). Two types of cells displayed distinct responses to LPS stimulation including 1) LPS induced the expression of CD11c and MIP-1□ in type B but not type A cells, 2) LPS elevated the level of CD 68 in type B cells but showed opposite effect for type A cells, 3) the LPS-mediated secretion of IL-1□, TNF-□, and nitric oxide was prominent for type B cells and to lesser extent for type A cells, and 4) LPS provoked the proliferation of type A but not type B cells. Interferon-□ (IFN-□) promoted the proliferation of both type A and type B cells, whereas it exerted differential effect on the nitric oxide production in both types of cells. Treatment with IFN-□ induced the production of nitric oxide in type B cells only, but it did increase the LPS-induced production of nitric oxide in type A cells. The effects of three kinds of A□ (A□25-35, oligomer form of A□1-42, and fibril form of A□1-42) and conditioned medium of A□-stimulated neuron (CMAN) on type A and type B microglia were further investigated. Only treatment of A□25-35 induced the expression of MIP-1□ in type A microglia. All three kinds of A□ provoked the secretion of TNF-□ in type B cells, whereas only A□25-35 induced the secretion of IL-1□ in both types of microglia. The A□25-35-CMAN exerted lesser cytotoxicity than the A□25-35 alone for type B microglia. The adjacent distance co-culture type A but not type B microglia with neurons showed protective effect on the toxicity of A□25-35. The conditioned medium from A□-stimulated microglia was used to elucidate the interaction of A□, microglia and neurons. The results demonstrated that the conditioned medium from either type A microglia treated with high concentration of A□25-35 or type B microglia treated with fibril A□1-42 exerted higher toxicity than A□ alone. Therefore, two types of microglia displayed specific characteristic in response to different insults in several respects including the expression of chemoattractive factor, secretion of proinflammatory cytokines, and neuron toxicity. These events may be implicated in the pathogenesis of AD.
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