Chronic copper exposure causes spatial memory impairment, selective loss of hippocampal synaptic proteins, and activation of PKR/eIF2α pathway in mice.
Chronic copper exposure causes spatial memory impairment, selective loss of hippocampal synaptic proteins, and activation of PKR/eIF2α pathway in mice.
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DOI：
10.3233/jad-140216
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发表时间：
2014-12
期刊：
影响因子：
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通讯作者：
Quan Ma;Ming Ying;Xiaojing Sui;Huimin Zhang;Hai-yan Huang;Lin-qing Yang;Xinfeng Huang;Z. Zhuang-Z.-Zhua
中科院分区：
文献类型：
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作者：
Quan Ma;Ming Ying;Xiaojing Sui;Huimin Zhang;Hai-yan Huang;Lin-qing Yang;Xinfeng Huang;Z. Zhuang-Z.-Zhua
铜是人体生长发育的必需元素;然而，过量摄入铜可能导致神经毒性。在这里，我们表明，慢性暴露于饮用水中的铜损害了小鼠的空间记忆，同时选择性丧失海马突触前蛋白synapsin 1和突触后密度蛋白（PSD）-93/95。铜暴露显示海马中的硝基酪氨酸和8-羟基脱氧鸟苷（8-OHdG）水平升高，这是氧化应激的两个标志物。同时，我们还发现铜暴露激活了双链RNA依赖性蛋白激酶（PKR），表现为Thr 451磷酸化PKR与总PKR的比例增加，并增加了其下游信号分子真核起始因子2α（eIF 2 α）在Ser 51的磷酸化。与PKR/eIF 2 α信号通路的激活一致，PKR/eIF 2 α信号通路被证明介导突触缺陷和认知障碍，激活转录因子4（ATF-4）的水平显著增加，ATF-4是eIF 2 α的下游信号分子和CREB介导的基因表达的阻遏物，而cAMP反应元件结合蛋白（CREB）的活性铜暴露导致CREB丝氨酸133位磷酸化水平降低，表明CREB失活。此外，促凋亡靶分子C/EBP同源蛋白（CHOP）的ATF-4的表达上调和海马神经元凋亡诱导铜暴露。综上所述，我们认为慢性铜暴露可能通过激活PKR/eIF 2 α信号通路，导致空间记忆障碍、突触蛋白选择性丢失和神经元凋亡。
Copper is an essential element for human growth and development; however, excessive intake of copper could contribute to neurotoxicity. Here we show that chronic exposure to copper in drinking water impaired spatial memory with simultaneous selective loss of hippocampal pre-synaptic protein synapsin 1, and post-synaptic density protein (PSD)-93/95 in mice. Copper exposure was shown to elevate the levels of nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG) in hippocampus, two markers of oxidative stress. Concurrently, we also found that copper exposure activated double stranded RNA-dependent protein kinase (PKR) as evidenced by increased ratio of phosphorylated PKR at Thr451 and total PKR and increased the phosphorylation of its downstream signaling molecule eukaryotic initiation factor 2α (eIF2α) at Ser51 in hippocampus. Consistent with activation of PKR/eIF2α signaling pathway which was shown to mediate synaptic deficit and cognitive impairment, the levels of activating transcription factor 4 (ATF-4), a downstream signaling molecule of eIF2α and a repressor of CREB-mediated gene expression, were significantly increased, while the activity of cAMP response elements binding protein (CREB) was inactivated as suggested by decreased phosphorylation of CREB at Ser133 by copper exposure. In addition, the expression of the pro-apoptotic target molecule C/EBP homology protein (CHOP) of ATF-4 was upregulated and hippocampal neuronal apoptosis was induced by copper exposure. Taken together, we propose that chronic copper exposure might cause spatial memory impairment, selective loss of synaptic proteins, and neuronal apoptosis through the mechanisms involving activation of PKR/eIF2α signaling pathway.