Rocha Nicole Kemberly R, Themoteo Rafael, Brentani Helena, Forlenza Orestes V, De Paula Vanessa De Jesus Rodrigues
Laboratório de Psicobiologia (LIM23), Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Laboratorio de Neurociencias (LIM27), Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Front Neurosci. 2020 Dec 1;14:579984. doi: 10.3389/fnins.2020.579984. eCollection 2020.
Neuronal-glial interactions are critical for brain homeostasis, and disruption of this process may lead to excessive glial activation and inadequate pro-inflammatory responses. Abnormalities in neuronal-glial interactions have been reported in the pathophysiology of Alzheimer's disease (AD), where lithium has been shown to exert neuroprotective effects, including the up-regulation of cytoprotective proteins. In the present study, we characterize by Gene Ontology (GO) the signaling pathways related to neuronal-glial interactions in response to lithium in a triple-transgenic mouse model of AD (3×-TgAD). Mice were treated for 8 months with lithium carbonate (Li) supplemented to chow, using two dose ranges to yield subtherapeutic working concentrations (Li1, 1.0 g/kg; and Li2, 2.0 g/kg of chow), or with standard chow (Li0). The hippocampi were removed and analyzed by proteomics. A neuronal-glial interaction network was created by a systematic literature search, and the selected genes were submitted to STRING, a functional network to analyze protein interactions. Proteomics data and neuronal-glial interactomes were compared by GO using ClueGo (Cytoscape plugin) with ≤ 0.05. The proportional effects of neuron-glia interactions were determined on three GO domains: (i) ; (ii) ; and (iii) . The gene ontology of this enriched network of genes was further stratified according to lithium treatments, with statistically significant effects observed in the Li2 group (as compared to controls) for the GO domains and . In the former, there was an even distribution of the interactions occurring at the following functions: "positive regulation of protein localization to membrane," "regulation of protein localization to cell periphery," "oligodendrocyte differentiation," and "regulation of protein localization to plasma membrane." In , interactions were also balanced for "myelin sheath" and "rough endoplasmic reticulum." We conclude that neuronal-glial interactions are implicated in the neuroprotective response mediated by lithium in the hippocampus of AD-transgenic mice. The effect of lithium on homeostatic pathways mediated by the interaction between neurons and glial cells are implicated in membrane permeability, protein synthesis and DNA repair, which may be relevant for the survival of nerve cells amidst AD pathology.
神经元与神经胶质细胞的相互作用对脑内环境稳定至关重要，该过程的破坏可能导致神经胶质细胞过度激活和促炎反应不足。在阿尔茨海默病（AD）的病理生理学中已报道了神经元与神经胶质细胞相互作用的异常，其中锂已显示出具有神经保护作用，包括上调细胞保护蛋白。在本研究中，我们通过基因本体论（GO）对AD三重转基因小鼠模型（3×-TgAD）中响应锂的神经元与神经胶质细胞相互作用相关的信号通路进行了表征。用添加到食物中的碳酸锂（Li）对小鼠进行8个月的治疗，使用两个剂量范围以产生亚治疗有效浓度（Li1，1.0 g/kg；Li2，2.0 g/kg食物），或使用标准食物（Li0）。取出海马体并通过蛋白质组学进行分析。通过系统的文献检索创建了一个神经元与神经胶质细胞相互作用网络，并将所选基因提交给STRING（一个用于分析蛋白质相互作用的功能网络）。使用ClueGo（Cytoscape插件）通过GO对蛋白质组学数据和神经元与神经胶质细胞相互作用组进行比较，P≤0.05。在三个GO结构域上确定了神经元与神经胶质细胞相互作用的比例效应：（i）；（ii）；和（iii）。根据锂处理对这个丰富的基因网络的基因本体进行进一步分层，在Li2组中观察到GO结构域和具有统计学显著效应（与对照组相比）。在前者中，在以下功能上发生的相互作用分布均匀：“蛋白质向膜的定位的正调控”、“蛋白质向细胞周边的定位的调控”、“少突胶质细胞分化”和“蛋白质向质膜的定位的调控”。在中，“髓鞘”和“粗面内质网”的相互作用也保持平衡。我们得出结论，神经元与神经胶质细胞的相互作用与锂在AD转基因小鼠海马体中介导的神经保护反应有关。锂对由神经元和神经胶质细胞之间的相互作用介导的稳态通路的影响与膜通透性、蛋白质合成和DNA修复有关，这可能与AD病理学中神经细胞的存活相关。
