Age-dependent astroglial vulnerability to hypoxia and glutamate: the role for erythropoietin.
Age-dependent astroglial vulnerability to hypoxia and glutamate: the role for erythropoietin.
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DOI：
10.1371/journal.pone.0077182
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Danielyan L
中科院分区：
文献类型：
--
作者：
Lourhmati A;Buniatian GH;Paul C;Verleysdonk S;Buecheler R;Buadze M;Proksch B;Schwab M;Gleiter CH;Danielyan L
谷氨酸(Glu)毒性浓度的细胞外蓄积是许多神经退行性疾病的一个特征，通常伴随着缺氧和这种神经介质的代谢受损。为了探讨促红细胞生成素(EPO)的多功能神经保护作用是否延伸到细胞外Glu水平的调节以及是否与年龄相关，在常氧和低氧条件下(NC和HC)，用1 mM Glu和/或人重组EPO同时处理幼年和培养的大鼠星形胶质原代细胞(APC)。促红细胞生成素促进星形胶质细胞摄取谷氨酸，尤其是在培养老化的APC中，对HC的摄取增加60%。此外，EPO还上调了谷氨酰胺合成酶(GS)的活性、谷氨酸-天冬氨酸转运体(GLAST)的表达和EPO的mRNA水平。EPO可减轻谷氨酸和低氧诱导的星形胶质细胞LDH释放。这些保护作用呈浓度依赖关系，且随着培养年龄的增加而增强。转染EPO受体(EPOR)-siRNA的APC细胞凋亡率增加4倍以上，GS酶活性降低2倍以上。我们的体内数据显示，在衰老过程中，APP/PS1小鼠及其野生型对照鼠脑匀浆中EPO的表达减少，EPOR的表达显著增加。比较APP/PS1和年龄匹配的WT对照组小鼠，发现在阿尔茨海默病(AD)模型小鼠中，EPOR的表达较强，而EPO的表达较弱。在体外低氧和谷氨酸诱导的星形胶质细胞损伤模型中，我们首次显示了星形胶质细胞分化程度(AGE)与EPO在平衡细胞外谷氨酸清除和代谢方面的有效性之间的直接关联。EPO和EPOR作为脑细胞衰老和神经退行性变的标志具有临床相关性，它们在AD转基因模型和WT对照中的表达水平的显著变化证明了这一点。
Extracellular accumulation of toxic concentrations of glutamate (Glu) is a hallmark of many neurodegenerative diseases, often accompanied by hypoxia and impaired metabolism of this neuromediator. To address the question whether the multifunctional neuroprotective action of erythropoietin (EPO) extends to the regulation of extracellular Glu-level and is age-related, young and culture-aged rat astroglial primary cells (APC) were simultaneously treated with 1mM Glu and/or human recombinant EPO under normoxic and hypoxic conditions (NC and HC). EPO increased the Glu uptake by astrocytes under both NC and especially upon HC in culture-aged APC (by 60%). Moreover, treatment with EPO up-regulated the activity of glutamine synthetase (GS), the expression of glutamate-aspartate transporter (GLAST) and the level of EPO mRNA. EPO alleviated the Glu- and hypoxia-induced LDH release from astrocytes. These protective EPO effects were concentration-dependent and they were strongly intensified with age in culture. More than a 4-fold increase in apoptosis and a 2-fold decrease in GS enzyme activity was observed in APC transfected with EPO receptor (EPOR)-siRNA. Our in vivo data show decreased expression of EPO and a strong increase of EPOR in brain homogenates of APP/PS1 mice and their wild type controls during aging. Comparison of APP/PS1 and age-matched WT control mice revealed a stronger expression of EPOR but a weaker one of EPO in the Alzheimer’s disease (AD) model mice. Here we show for the first time the direct correlation between the extent of differentiation (age) of astrocytes and the efficacy of EPO in balancing extracellular glutamate clearance and metabolism in an in-vitro model of hypoxia and Glu-induced astroglial injury. The clinical relevance of EPO and EPOR as markers of brain cells vulnerability during aging and neurodegeneration is evidenced by remarkable changes in their expression levels in a transgenic model of AD and their WT controls.
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影响因子：
1
作者：
Arabpoor Z;Hamidi G;Rashidi B;Shabrang M;Alaei H;Sharifi MR;Salami M;Dolatabadi HR;Reisi P
通讯作者：
Reisi P
影响因子：
3.2
作者：
Abdel-Mageed, AB;Zhao, FS;Agrawal, KC
通讯作者：
Agrawal, KC
影响因子：
4.2
作者：
Buniatian, GH;Hartmann, HJ;Gebhardt, R
通讯作者：
Gebhardt, R
影响因子：
4.7
作者：
Kobayashi, S;Millhorn, DE
通讯作者：
Millhorn, DE
影响因子：
9.9
作者：
MASLIAH, E;MALLORY, M;TERRY, RD
通讯作者：
TERRY, RD