Astrocytes and glutamate homoeostasis in Alzheimer's disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex.
Astrocytes and glutamate homoeostasis in Alzheimer's disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex.
复制标题
DOI：
10.1042/an20130017
复制
发表时间：
2013-10-07
期刊：
影响因子：
4.7
通讯作者：
Rodríguez JJ
中科院分区：
文献类型：
--
作者：
Kulijewicz-Nawrot M;Syková E;Chvátal A;Verkhratsky A;Rodríguez JJ
星形胶质细胞控制组织平衡，因此定义了CNS（中枢神经系统）的稳态和功能。星形胶质细胞作为主要的稳态细胞，是各种形式的神经病理学的基础，包括AD（阿尔茨海默病）。AD是一种进行性神经退行性疾病，其特征在于由于记忆相关区域（包括mPFC（内侧前额叶皮质））中的特定病变而导致认知功能丧失。在这里，我们分析了GS（谷氨酰胺合成酶）和GLT-1（谷氨酸转运蛋白-1）的表达在星形胶质细胞的mPFC在AD的进展过程中在一个三转基因小鼠模型（3xTg-AD）。GS是一种星形胶质细胞特异性酶，负责谷氨酸在细胞内转化为谷氨酰胺，而谷氨酸从细胞外空间的去除主要是通过星形胶质细胞特异性GLT-1完成的。我们发现数字密度显著降低早期至中期的GS阳性星形胶质细胞（Nv，细胞/mm 3）（1-9个月;与对照动物相比，1月龄时降低17%，6月龄时降低27%，9月龄时降低27%），同时GS表达降低（通过蛋白质印迹法测定），其在6月龄开始并持续至12月龄。然而，我们没有发现GLT-1表达的任何变化，这意味着完整的谷氨酸摄取机制。我们的研究结果表明，GS表达的减少可能是重要的星形胶质细胞依赖的谷氨酸-谷氨酰胺转换途径逐渐下降的基础，这反过来又可能损害谷氨酸体内平衡，导致突触连接失败，认知和记忆缺陷。
Astrocytes control tissue equilibrium and hence define the homoeostasis and function of the CNS (central nervous system). Being principal homoeostatic cells, astroglia are fundamental for various forms of neuropathology, including AD (Alzheimer's disease). AD is a progressive neurodegenerative disorder characterized by the loss of cognitive functions due to specific lesions in mnesic-associated regions, including the mPFC (medial prefrontal cortex). Here, we analyzed the expression of GS (glutamine synthetase) and GLT-1 (glutamate transporter-1) in astrocytes in the mPFC during the progression of AD in a triple-transgenic mouse model (3xTg-AD). GS is an astrocyte-specific enzyme, responsible for the intracellular conversion of glutamate into glutamine, whereas the removal of glutamate from the extracellular space is accomplished mainly by astroglia-specific GLT-1. We found a significant decrease in the numerical density (Nv, cells/mm3) of GS-positive astrocytes from early to middle ages (1–9 months; at the age of 1 month by 17%, 6 months by 27% and 9 months by 27% when compared with control animals) in parallel with a reduced expression of GS (determined by Western blots), which started at the age of 6 months and was sustained up to 12 months of age. We did not, however, find any changes in the expression of GLT-1, which implies an intact glutamate uptake mechanism. Our results indicate that the decrease in GS expression may underlie a gradual decline in the vital astrocyte-dependent glutamate–glutamine conversion pathway, which in turn may compromise glutamate homoeostasis, leading towards failures in synaptic connectivity with deficient cognition and memory.