Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease
Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease
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低剂量口服铜治疗改变阿尔茨海默氏病小鼠模型的海马磷酸蛋白质组谱并扰乱线粒体功能
DOI：
10.1016/j.freeradbiomed.2019.03.002
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发表时间：
2019-05-01
影响因子：
7.4
通讯作者：
Yang, Xifei
中科院分区：
文献类型：
--
作者：
Chen, Chongyang;Jiang, Xin;Yang, Xifei
过量的铜会引起神经毒性，并导致一些神经系统疾病的发生；然而，铜的神经毒性及其潜在机制仍知之甚少。我们使用蛋白质组学和磷酸蛋白质组学来量化野生型和 3xTg-AD 小鼠海马中的蛋白质变化，这两种小鼠均在 6 个月大时接受添加或不添加氯化铜（0.13 ppm 浓度）的饮用水 2 个月的治疗。从 1406 个磷蛋白中总共鉴定出 3960 个独特的磷酸肽（5290 个磷酸化位点）。差异表达的磷蛋白涉及神经元和突触功能、转录调节、能量代谢和线粒体功能。此外，对野生型小鼠进行低剂量铜治疗会降低海马线粒体拷贝数、线粒体生物发生并扰乱线粒体动力学。这些变化与过氧化氢 (H2O2) 产生增加、细胞色素氧化酶活性降低和 ATP 含量降低有关。在 3xTg-AD 小鼠中，相同的低剂量口服铜治疗增加了轴突变性，这与 T286 处 Camk2 α 磷酸化的改变和丝裂原激活蛋白激酶 (ERK1/2) 的磷酸化有关，其中涉及长时程增强 (LTP) 信号传导。线粒体功能障碍主要与糖原合酶激酶3β（GSK3β）和丝氨酸/苏氨酸蛋白磷酸酶2B催化亚基α同种型（Ppp3ca）磷酸化水平的变化有关，这涉及线粒体生物发生信号传导。总之，低剂量口服铜治疗改变了涉及线粒体、突触和轴突完整性的关键海马蛋白的磷酸化。这些数据显示，过量的铜会加速观察到的一些 AD 变化的早期事件，表明过量的循环铜有可能扰乱野生型小鼠的大脑功能，并加剧 AD 小鼠模型的神经退行性变化。
Excessive copper can cause neurotoxicity and contribute to the development of some neurological diseases; however, copper neurotoxicity and the potential mechanisms remain poorly understood. We used proteomics and phosphoproteomics to quantify protein changes in the hippocampus of wild-type and 3xTg-AD mice, both of which were treated at 6 months of age with 2 months of drinking water with or without added copper chloride (0.13 ppm concentration). A total of 3960 unique phosphopeptides (5290 phosphorylation sites) from 1406 phosphoproteins was identified. Differentially expressed phosphoproteins involved neuronal and synaptic function, transcriptional regulation, energy metabolism and mitochondrial function. In addition, low-dose copper treatment of wild-type mice decreased hippocampal mitochondrial copy number, mitochondrial biogenesis and disrupted mitochondrial dynamics; these changes were associated with increased hydrogen peroxide production (H2O2), reduced cytochrome oxidase activity and decreased ATP content. In 3xTg-AD mice, identical low-dose oral copper treatment increased axonal degeneration, which was associated with altered phosphorylation of Camk2 alpha at T286 and phosphorylation of mitogen-activated protein kinase (ERK1/2), which involved long-term potentiation (LTP) signaling. Mitochondrial dysfunction was mainly related to changes in phosphorylation levels of glycogen synthase kinase-3 beta (GSK3 beta) and serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (Ppp3ca), which involved mitochondrial biogenesis signaling. In sum, low-dose oral copper treatment changes the phosphorylation of key hippocampal proteins involved in mitochondrial, synaptic and axonal integrity. These data showing that excess of copper speeds some early events of AD changes observed suggest that excess circulating copper has the potential to perturb brain function of wild-type mice and exacerbate neurodegenerative changes in a mouse model of AD.