AUTHOR=Tanaka Ken-ichiro , Kawahara Masahiro TITLE=Copper Enhances Zinc-Induced Neurotoxicity and the Endoplasmic Reticulum Stress Response in a Neuronal Model of Vascular Dementia JOURNAL=Frontiers in Neuroscience VOLUME=11 YEAR=2017 URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2017.00058 DOI=10.3389/fnins.2017.00058 ISSN=1662-453X 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.