Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 43, Issue 4, Pages 1413-1427Publisher
IOS PRESS
DOI: 10.3233/JAD-140216
Keywords
Copper; double stranded RNA-dependent protein kinase (PKR); eukaryotic initiation factor 2 alpha (eIF2 alpha); spatial learning and memory; synaptic proteins
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Funding
- NSFC (the National Natural Science Foundation of China) [81102154]
- Medical Scientific Research Foundation of Guangdong Province [A2013598]
- Shenzhen Scheme of Science and Technology (Medicine and Health) [201302148]
- Shenzhen Special Fund Project on Strategic Emerging Industry Development [JCYJ20130329103949650, JCYJ20120613172906373]
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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 strandedRNA-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 2 alpha (eIF2 alpha) at Ser51 in hippocampus. Consistent with activation of PKR/eIF2 alpha 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 eIF2 alpha 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/eIF2 alpha signaling pathway.
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