title: Copper Enhances Zinc-Induced Neurotoxicity and the Endoplasmic Reticulum Stress Response in a Neuronal Model of Vascular Dementia.
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, includingCHOP, GADD34, andATF4. 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.
authors.affiliation: Department of Bio Analytical Chemistry, Musashino University Nishitokyo-shi, Japan.
authors.forename: Ken-Ichiro
authors.initials: KI
authors.lastname: Tanaka
authors.affiliation: Department of Bio Analytical Chemistry, Musashino University Nishitokyo-shi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
keywords: ER stress; dementia; ischemia; metal–metal interaction; neurotoxicity; synapse