Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells
Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells
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DOI：
10.3233/jad-160297
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Wu, Yan
中科院分区：
文献类型：
--
作者：
Li, Yan;Chang, Lirong;Wu, Yan
早期阿尔茨海默病（AD）的特征在于突触功能障碍，这是一种涉及淀粉样蛋白-β（A β）和N-甲基-D-天冬氨酸受体（NMDAR）的可溶性寡聚体的现象。在这里，我们证明了星形胶质细胞表达NMDAR，因此有可能调节A β的突触毒性作用。我们发现，两个主要的NMDAR亚基，GluN 2A和GluN 2B的特异性药理学拮抗作用，加剧了A β诱导的突触毒性，首次表明，星形胶质细胞GluN 2A和GluN 2B介导突触保护。从A β和NMDAR发挥重要作用的阿尔茨海默病的致病机制的角度来看，这些观察结果是惊人的，因为神经元GluN 2A和GluN 2B是众所周知的神经变性调节剂。我们进行了初步研究，以了解星形胶质细胞和神经元GluN 2A和GluN 2B在促进突触存活中的差异作用的基础，并确定了星形胶质细胞产生的神经营养因子，神经生长因子β（β-NGF），作为星形胶质细胞GluN 2A和GluN 2B激活的突触保护作用的可能介质。提出的结果表明，星形胶质细胞可能是合适的药物靶点，用于预防和/或延迟AD早期阶段发生的突触丢失。
Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (A beta) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of A beta. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates A beta-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer's disease, in which A beta and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor beta (beta-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD.