Synapse degeneration correlates strongly with cognitive impairments in Alzheimer's disease (AD) patients. Soluble Amyloid-beta (Aβ) oligomers are thought as the major trigger of synaptic malfunctions. Our earlier studies have demonstrated that Aβ oligomers interfere with synaptic function through N-methyl-D-aspartate receptors (NMDARs). Our recent in vitro study found the neuroprotective role of astrocytic GluN2A in the promotion of synapse survival and identified nerve growth factor (NGF) derived from astrocytes, as a likely mediator of astrocytic GluN2A buffering against Aβ synaptotoxicity. Our present in vivo study focused on exploring the precise mechanism of astrocytic GluN2A influencing Aβ synaptotoxicity through regulating NGF. We generated an adeno-associated virus (AAV) expressing an astrocytic promoter (GfaABC1D) shRNA targeted to Grin2a (the gene encoding GluN2A) to perform astrocyte-specific Grin2a knockdown in the hippocampal dentate gyrus, after 3 weeks of virus vector expression, Aβ were bilaterally injected into the intracerebral ventricle. Our results showed that astrocyte-specific knockdown of Grin2a and Aβ application both significantly impaired spatial memory and cognition, which associated with the reduced synaptic proteins PSD95, synaptophysin and compensatory increased NGF. The reduced astrocytic GluN2A can counteract Aβ-induced compensatory protective increase of NGF through regulating pNF-κB, Furin and VAMP3, which modulating the synthesis, mature and secretion of NGF respectively. Our present data reveal, for the first time, a novel mechanism of astrocytic GluN2A in exerting protective effects on synapses at the early stage of Aβ exposure, which may contribute to establish new targets for AD prevention and early therapy.

中文翻译：

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敲除星形胶质细胞 Grin2a 通过调节神经生长因子加重 β-淀粉样蛋白诱导的记忆和认知缺陷

突触变性与阿尔茨海默病 (AD) 患者的认知障碍密切相关。可溶性淀粉样蛋白-β (Aβ) 寡聚体被认为是突触功能障碍的主要触发因素。我们早期的研究表明，Aβ 寡聚体通过 N-甲基-D-天冬氨酸受体 (NMDAR) 干扰突触功能。我们最近的体外研究发现了星形胶质细胞 GluN2A 在促进突触存活中的神经保护作用，并确定了源自星形胶质细胞的神经生长因子 (NGF) 作为星形胶质细胞 GluN2A 缓冲 Aβ 突触毒性的可能介质。我们目前的体内研究侧重于探索星形胶质细胞 GluN2A 通过调节 NGF 影响 Aβ 突触毒性的确切机制。我们生成了一种腺相关病毒 (AAV)，该病毒表达一个星形胶质细胞启动子 (GfaABC1D) shRNA，靶向 Grin2a（编码 GluN2A 的基因），在海马齿状回中进行星形胶质细胞特异性 Grin2a 敲低，病毒载体表达 3 周后，Aβ 是双侧注入脑室。我们的研究结果表明，星形胶质细胞特异性敲除 Grin2a 和 Aβ 应用均显着损害空间记忆和认知，这与减少的突触蛋白 PSD95、突触素和代偿性增加的 NGF 相关。减少的星形胶质细胞 GluN2A 可以通过调节 pNF-κB、弗林蛋白酶和 VAMP3 来抵消 Aβ 诱导的 NGF 代偿性保护性增加，它们分别调节 NGF 的合成、成熟和分泌。我们目前的数据首次揭示，