碩士 / 國立陽明大學 / 神經科學研究所 / 92 / 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.
| Identifer | oai:union.ndltd.org:TW/092YM005291002 |
| Date | January 2004 |
| Creators | Hung-I Tsai, 蔡弘毅 |
| Contributors | Yun-Chia Chou, 周韻家 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 71 |
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