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研究生(外文):Hung-I Tsai
論文名稱(外文):Mechanistic study of cholesterol deficiency enhancing glutamate-induced cytotoxicity to hippocampal astrocytes
指導教授(外文):Yun-Chia Chou
外文關鍵詞:cholesterolcholesterol deficiencygliaastrocyteglutamateglutamine synthetase
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膽固醇對於哺乳動物的腦功能行使扮演著重要的角色。過去我們實驗室利用大白鼠的海馬迴星狀神經膠細胞培養作為實驗材料,發現當降低星狀神經膠細胞膽固醇含量, 所受到麩胺酸誘發的細胞死亡更為嚴重,但這個現象在海馬迴神經細胞上沒有發現。本論文的研究工作是要探討可能有哪些機制造成海馬迴星狀神經膠細胞膽固醇短缺時會加劇麩胺酸誘發的細胞死亡。
我發現到用lovastatin處理細胞時同時加入GGPP或者是FPP,可以減緩低海馬迴星狀神經膠細胞膽固醇含量加劇麩胺酸誘發的細胞死亡現象,GGPP和FPP是影響small GTPase protein作用的重要分子。此外在膽固醇短缺的海馬迴星狀神經膠細胞上可以發現到ERK1/2的磷酸化顯著上升,而ERK1/2是small GTPase protein的Ras訊號傳遞路徑下游分子,推測膽固醇短缺時海馬迴星狀神經膠細胞訊號傳遞會有所改變。此外我亦觀察到膽固醇短缺時海馬迴星狀神經膠細胞細胞形態明顯改變,同時actin結構有瓦解的現象,這樣的情況在海馬迴神經細胞上卻沒有見到,若在lovastatin處理海馬迴星狀神經膠細胞時同時加入GGPP或者是FPP,可減少細胞形態改變和actin結構的瓦解。當膽固醇短缺,對於海馬迴星狀神經膠細胞特有代謝麩胺酸的蛋白質麩胺醯酸轉化酶,我觀察到其表現量和活性有明顯下降,此外海馬迴星狀神經膠細胞膽固醇短缺時,可以觀察到細胞外有較多先以[3H]標記的天門冬胺酸 (麩胺酸的類似物)累積,推測膽固醇短缺時,海馬迴星狀神經膠細胞內麩胺醯酸轉化酶表現量和活性下降,使細胞內麩胺酸濃度上升,而較易溢出細胞外,造成膽固醇短缺的海馬迴星狀神經膠細胞外麩胺酸的累積量較高,可能因此加劇麩胺酸誘發的細胞死亡。
Cholesterol, a molecule critical for cellular function, is found in particular high concentration in the brain and has been implicated to synaptic plasticity and neuronal regeneration. We previously demonstrated that cholesterol deficiency exacerbated glutamate (Glu)-induced cytotoxicity to hippocampal glia, but not to neurons, in primary cultures. This study was undertaken to investigate the mechanism underlying the enhanced vulnerability of cholesterol-deficient astrocytes to Glu-induced cytotoxicity.
The detrimental effect of cholesterol depletion was partially abolished by both geranylgeranylpyrophosphate and farnesylpyrophosphate, molecules essential for prenyl modification of the small GTP-binding protein such as Ras. Cholesterol depletion by a combined treatment of lovastatin and β-cyclodextrin increased the phosphorylation of ERK 1/2, a downstream effector of Ras, in hippocampal astrocytes. In addition, we observed morphological changes, accompanied by disorganization of actin bundles in astrocytes of cholesterol deficiency. After cholesterol deprivation, there was a marked efflux of exogenous [3H] D-aspartate, a Glu analogue, from astrocytes upon stimulation by Glu. Cholesterol deprivation decreased the expression and the activity of glutamine synthetase, which converts Glu into glutamine.
We conclude that cholesterol deprivation affects signal transduction and impairs the integrity of cytoskeleton structure in astrocytes. Moreover, cholesterol depletion causes the buildup of a concentration gradient favoring Glu efflux from astrocytes. The elevated level of extracellular Glu thus accelerates the Glu-cytotoxicity to cholesterol deficient astrocytes.
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