D-半乳糖致小鼠脑衰老早期阶段星形胶质细胞的活化及其作用机制
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摘要
我们前期的研究表明反应性星形胶质细胞增生参与了D-半乳糖诱导的脑衰老病理过程。然而,星形胶质细胞活化是发生在神经元死亡之前,还是对神经元变性后的继发反应,仍有待确定。本实验研究该衰老模型早期阶段海马神经元的损伤以及星形胶质细胞的活化,并进一步探索活化的星形胶质细胞是否能增加谷氨酸摄取能力,从而防止由D-半乳糖注射引起的谷氨酸兴奋性毒性。成年雄性ICR小鼠随机分为2组:D-半乳糖模型组和正常对照组,分别每日腹腔注射200mg/kg的2%D-半乳糖或等量生理盐水,持续2周。采用生化分光光度法检测海马区氧化应激水平;用Hoechst染色以及caspase-3免疫组化染色观察神经元的凋亡情况;用神经微管蛋白III和突触素免疫组化观察神经元突起和突触终末的改变;用免疫荧光方法观察谷氨酸和c-fos的表达;用免疫组化方法观察胶质纤维酸性蛋白(GFAP)以及其谷氨酸转运体1 (GLT-1)、谷氨酸天冬氨酸转运体(GLAST)和水通道蛋白4 (AQP4)的表达水平。与对照组相比,持续注射2周的D-半乳糖并没有导致显著的氧化/抗氧化参数改变,也没有出现海马神经元的损失或凋亡。相比之下,GFAP免疫组化显示在D-半乳糖注射小鼠的海马区反应性的星形胶质细胞比例显著增加。此外,与谷氨酸和c-Fos蛋白荧光双标所示的海马区谷氨酸能神经元激活结果相一致,模型组海马区星形胶质细胞膜上GLT-1和AQP4表达也显著增加,但GLAST上调不明显。这些证据提示星形胶质细胞活化在脑衰老的早期阶段是原发性的。而且,通过上调谷氨酸和水的转运蛋白,活化的星形胶质细胞可能有助于维持衰老早期脑内谷氨酸和水的平衡。因此,调节星形胶质细胞的功能可能会成为延缓脑衰老的一种新靶标。
Our previous study demonstrated that reactive astrogliosis is involved in the D-galactose-induced brain ageing. However, whether activation of astrocytes precedes or follows neuron cell death remains to be determined. Therefore, we investigated neuronal damage and astrocyte activation in the hippocampus at the early stage of this model. We also evaluated whether reactive astrocytes enhance the capabilities of glutamate uptake and water transport to prevent glutamate excitotoxicity induced by D-galactose injection. To prepare ageing model by D-galactose, the mice were randomly divided into 2 groups: D-galactose group and control group, receiving daily intraperitoneal injection of 200mg/kg 2% D-galactose or saline respectively for 2 weeks. After 2 weeks of administration, we detected biochemical levels of oxidative stress in the hippocampus by biochemical spectrophotometer. We observed neuronal apoptosis by Hoechst staining and caspase-3 immunohistochemistry. We also observed changes neuronal processes and axonal terminals in the hippocampus of two groups by using immunohistochemistryβ-tubulin III and synaptophysin. Moreover, we analysized glutamate and c-fos expression by immunofluorescence, and observed glial fibrillary acidic protein (GFAP) and its membrane glutamate transporter-1 (GLT1), glutamate-aspartate transporter (GLAST), and aquaporin-4 (AQP4) expression by immunohistochemistry. Biochemical analyses showed that mice injected with D-galactose for 2 week had no obvious changes in brain oxidative and antioxidative parameters compared with vehicle controls. Pathological results also indicated no obvious impairments in neuronal soma, process and synapse in the hippocampus of model mice. In contrast, GFAP immunohistochemistry revealed a prominent increase in the percentage of reactive hippocampal astrocytes in D-galactose-treated mice. Moreover, the increased immunostaining levels of GLT1 and AQP4, but not GLAST were observed in the model hippocampus, which were consistent with activation of hippocampal glutamatergic neurons as revealed by glutamate and c-Fos protein double immunostaining. These results suggest that astrocyte reactivity is a primary event during the ageing process. Moreover, these findings indicate that, via up-regulations of glutamate and water transport proteins, reactivated astrocytes maintain glutamate homeostasis at the early stage of brain ageing. Thus, regulating the plasticity of astrocytes may be a new target to delay brain ageing.
Our previous study demonstrated that reactive astrogliosis is involved in the D-galactose-induced brain ageing. However, whether activation of astrocytes precedes or follows neuron cell death remains to be determined. Therefore, we investigated neuronal damage and astrocyte activation in the hippocampus at the early stage of this model. We also evaluated whether reactive astrocytes enhance the capabilities of glutamate uptake and water transport to prevent glutamate excitotoxicity induced by D-galactose injection. To prepare ageing model by D-galactose, the mice were randomly divided into 2 groups: D-galactose group and control group, receiving daily intraperitoneal injection of 200mg/kg 2% D-galactose or saline respectively for 2 weeks. After 2 weeks of administration, we detected biochemical levels of oxidative stress in the hippocampus by biochemical spectrophotometer. We observed neuronal apoptosis by Hoechst staining and caspase-3 immunohistochemistry. We also observed changes neuronal processes and axonal terminals in the hippocampus of two groups by using immunohistochemistryβ-tubulin III and synaptophysin. Moreover, we analysized glutamate and c-fos expression by immunofluorescence, and observed glial fibrillary acidic protein (GFAP) and its membrane glutamate transporter-1 (GLT1), glutamate-aspartate transporter (GLAST), and aquaporin-4 (AQP4) expression by immunohistochemistry. Biochemical analyses showed that mice injected with D-galactose for 2 week had no obvious changes in brain oxidative and antioxidative parameters compared with vehicle controls. Pathological results also indicated no obvious impairments in neuronal soma, process and synapse in the hippocampus of model mice. In contrast, GFAP immunohistochemistry revealed a prominent increase in the percentage of reactive hippocampal astrocytes in D-galactose-treated mice. Moreover, the increased immunostaining levels of GLT1 and AQP4, but not GLAST were observed in the model hippocampus, which were consistent with activation of hippocampal glutamatergic neurons as revealed by glutamate and c-Fos protein double immunostaining. These results suggest that astrocyte reactivity is a primary event during the ageing process. Moreover, these findings indicate that, via up-regulations of glutamate and water transport proteins, reactivated astrocytes maintain glutamate homeostasis at the early stage of brain ageing. Thus, regulating the plasticity of astrocytes may be a new target to delay brain ageing.
引文
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