星形胶质细胞 N-甲基-D-天冬氨酸受体通过调节神经生长因子来保护海马神经元免受β淀粉样肽 142 诱导的突触毒性。

Astrocytic N-Methyl-D-Aspartate Receptors Protect the Hippocampal Neurons Against Amyloid-β142-Induced Synaptotoxicity by Regulating Nerve Growth Factor.

机构信息

Department of Anatomy, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.

出版信息

J Alzheimers Dis. 2022;85(1):167-178. doi: 10.3233/JAD-210730.

DOI:10.3233/JAD-210730

PMID:34776441

Abstract

BACKGROUND

Soluble oligomeric amyloid-β (Aβ)-induced synaptic dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. Mounting evidence has suggested N-methyl-D-aspartate receptors (NMDARs) play an important role in Aβ-induced synaptotoxicity. Originally NMDARs were believed to be expressed exclusively in neurons; however, recent two decades studies have demonstrated functional NMDARs present on astrocytes. Neuronal NMDARs are modulators of neurodegeneration, while our previous initial study found that astrocytic NMDARs mediated synaptoprotection and identified nerve growth factor (NGF) secreted by astrocytes, as a likely mediator, but how astrocytic NMDARs protect neurons against Aβ-induced synaptotoxicity through regulating NGF remains unclear.

OBJECTIVE

To achieve further insight into the mechanism of astrocytic NMDARs oppose Aβ-induced synaptotoxicity through regulating NGF.

METHODS

With the primary hippocampal neuronal and astrocytic co-cultures, astrocytes were pretreated with agonist or antagonist of NMDARs before Aβ142 oligomers application to neuron-astrocyte co-cultures. Western blot, RT-PCR, etc., were used for the related proteins evaluation.

RESULTS

Activation of astrocytic NMDARs can significantly mitigate Aβ142-induced loss of PSD-95 and synaptophysin through increasing NGF release. Blockade of astrocytic NMDARs inhibited Aβ-induced compensatory protective NGF increase in protein and mRNA levels through modulating NF-κB of astrocytes. Astrocytic NMDARs activation can enhance Aβ-induced Furin increase, and blockade of astrocytic NMDARs inhibited Aβ-induced immunofluorescent intensity elevation of vesicle trafficking protein VAMP3 and NGF double-staining.

CONCLUSION

Astrocytic NMDARs oppose Aβ-induced synaptotoxicity through modulating the synthesis, maturation, and secretion of NGF in astrocytes. This new information may contribute to the quest for specific targeted strategy of intervention to delay the onset of AD.

摘要

背景

可溶性寡聚体淀粉样蛋白-β（Aβ）诱导的突触功能障碍是阿尔茨海默病（AD）发病机制中的早期事件。越来越多的证据表明，N-甲基-D-天冬氨酸受体（NMDAR）在 Aβ诱导的突触毒性中发挥重要作用。最初认为 NMDAR 仅在神经元中表达；然而，最近二十年的研究表明星形胶质细胞中存在功能性 NMDAR。神经元 NMDAR 是神经退行性变的调节剂，而我们之前的初步研究发现星形胶质细胞 NMDAR 介导突触保护，并确定星形胶质细胞分泌的神经生长因子（NGF）可能作为一种介质，但星形胶质细胞 NMDAR 如何通过调节 NGF 来保护神经元免受 Aβ 诱导的突触毒性仍不清楚。

目的

深入了解星形胶质细胞 NMDAR 通过调节 NGF 对抗 Aβ 诱导的突触毒性的机制。

方法

采用原代海马神经元和星形胶质细胞共培养，在 Aβ142 寡聚体应用于神经元-星形胶质细胞共培养物之前，用 NMDAR 激动剂或拮抗剂预处理星形胶质细胞。采用 Western blot、RT-PCR 等方法评估相关蛋白。

结果

激活星形胶质细胞 NMDAR 可通过增加 NGF 释放，显著减轻 Aβ142 诱导的 PSD-95 和突触小泡蛋白的丢失。星形胶质细胞 NMDAR 阻断可通过调节 NF-κB 抑制 Aβ 诱导的补偿性保护 NGF 蛋白和 mRNA 水平增加。星形胶质细胞 NMDAR 激活可增强 Aβ 诱导的弗林增加，而星形胶质细胞 NMDAR 阻断可抑制 Aβ 诱导的囊泡转运蛋白 VAMP3 和 NGF 双重染色的免疫荧光强度升高。