Abstract
Zinc (Zn), an essential trace element, is secreted by synaptic vesicles during neuronal excitation and plays several critical roles in neuronal information processing. However, excess Zn ion (Zn2+) is neurotoxic and has a causative role in the pathogenesis of vascular dementia. Here, we investigated the molecular mechanism of Zn2+-induced neurotoxicity by using immortalized hypothalamic neurons (GT1-7 cells), which are more vulnerable than other neuronal cells to Zn2+. We examined the effects of other metal ions on the Zn2+-induced neurotoxicity in these cells and found that sub-lethal concentrations of copper ion (Cu2+) markedly exacerbated Zn2+-induced neurotoxicity. The co-administration of Cu2+ and Zn2+ also significantly increased the expression of genes related to the endoplasmic reticulum's stress response, including CHOP, GADD34, and ATF4. Similar to Zn2+, Cu2+ is stored in presynaptic vesicles and secreted during neuronal excitation. Thus, based on our results, we hypothesize here that Cu2+ interacts with Zn2+ in the synapse to synergistically promote neuronal death and significantly influence the pathogenesis of vascular dementia.