Copper Enhances Zinc-Induced Neurotoxicity and the Endoplasmic Reticulum Stress Response in a Neuronal Model of Vascular Dementia

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 (Zn(2+)) is neurotoxic and has a causative role in the pathogenesis of vascular dementia. Here, we investigated the molecular mechanism of Zn(2+)-induced neurotoxicity by using immortalized hypothalamic neurons (GT1-7 cells), which are more vulnerable than other neuronal cells to Zn(2+). We examined the effects of other metal ions on the Zn(2+)-induced neurotoxicity in these cells and found that sub-lethal concentrations of copper ion (Cu(2+)) markedly exacerbated Zn(2+)-induced neurotoxicity. The co-administration of Cu(2+) and Zn(2+) also significantly increased the expression of genes related to the endoplasmic reticulum's stress response, including CHOP, GADD34, and ATF4. Similar to Zn(2+), Cu(2+) is stored in presynaptic vesicles and secreted during neuronal excitation. Thus, based on our results, we hypothesize here that Cu(2+) interacts with Zn(2+) in the synapse to synergistically promote neuronal death and significantly influence the pathogenesis of vascular dementia.