Chronic Copper Exposure Causes Spatial Memory Impairment, Selective Loss of Hippocampal Synaptic Proteins, and Activation of PKR/eIF2α Pathway in Mice

Article type: Research Article

Authors: Ma, Quan^{a; b; 1} | Ying, Ming^{b; 1} | Sui, Xiaojing^a | Zhang, Huimin^a | Huang, Haiyan^a | Yang, Linqing^a | Huang, Xinfeng^a | Zhuang, Zhixiong^a | Liu, Jianjun^a | Yang, Xifei^{a; *}

Affiliations: [a] Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China | [b] College of Life Sciences, Shenzhen University, Shenzhen, China

Correspondence: [*] Correspondence to: Dr. Xifei Yang, No 8, Longyuan Road, Nanshan District, Shenzhen 518055, China. Tel.: +86 755 25601914; Fax: +86 755 25508584; E-mail: xifeiyang@gmail.com.

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: Copper, double stranded RNA-dependent protein kinase (PKR), eukaryotic initiation factor 2α (eIF2α), spatial learning and memory, synaptic proteins

DOI: 10.3233/JAD-140216

Journal: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1413-1427, 2015