Crosstalk of copper and zinc in the pathogenesis of vascular dementia

Abstract

Copper and zinc are essential for normal brain functions. Both are localized in presynaptic vesicles and are secreted into synaptic clefts during neuronal excitation. Despite their significance, excesses of copper and zinc are neurotoxic. In particular, excess zinc after transient global ischemia plays a central role in the ischemia-induced neurodegeneration and pathogenesis of vascular type senile dementia. We previously found that sub-lethal concentrations of copper remarkably exacerbated zinc-induced neurotoxicity, and we investigated the molecular pathways of copper-enhanced zinc-induced neurotoxicity. The endoplasmic reticulum stress pathway, the stress-activated protein kinases/ c-Jun amino-terminal kinases pathway, and mitochondrial energy production failure were revealed to be involved in the neurodegenerative processes. Regarding the upstream factors of these pathways, we focused on copper-derived reactive oxygen species and the disruption of calcium homeostasis. Because excess copper and zinc may be present in the synaptic clefts during ischemia, it is possible that secreted copper and copper-induced reactive oxygen species may enhance zinc neurotoxicity and eventually contribute to the pathogenesis of vascular type senile dementia.

Dietary Trace Elements and the Pathogenesis of Neurodegenerative Diseases

“…However, under pathological conditions such as transient global ischemia, sustained excitation of neurons occurs for prolonged periods in broad areas of the brain, and excess Zn and Cu are simultaneously secreted into the same synaptic clefts for a long period of time. We have demonstrated that a sublethal concentration of Cu (5 µM) significantly exaggerated 30 µM Zn-induced neurotoxicity (molar ratio of Zn:Cu = 6:1) [123]. Therefore, it is possible that the coexistence of Cu triggers the production of ROS and cooperatively enhances Zn-induced neurotoxicity, finally causing vascular-type dementia.…”

“…Several antioxidants were found to attenuate Cu-enhanced Zn-induced neurotoxicity. Therefore, Cu may collaborate with Zn and play key roles in Zn-induced neurotoxicity by producing ROS, finally leading to the pathogenesis of VD [123].…”

Uncovering Novel Therapeutic Targets for Parkinson’s Disease

“…This leads to oxidative stress and endoplasmic reticulum stress that may finally lead to neurodegeneration. 44 There is more evidence of zinc and copper related toxicities leading to AD. However, this also may be involved in PD.…”

Zinc in Human Health and Infectious Diseases

“…Moreover, zinc supplementation in high doses compromises copper uptake and vice versa. Adequate zinc and copper homeostasis is known to be important for decades and an altered copper/zinc ratio is found in multiple diseases, such as neurodegenerative disorders [ 125 , 126 ], hepatocellular and gastric carcinoma [ 127 , 128 ], immunological disorders such as sickle cell disease [ 129 ], and bacterial and viral infectious diseases such as leishmaniosis or COVID-19 [ 130 , 131 ]. In future, it may possible that the copper/zinc ratio may be considered as a biomarker for disease or for mortality in the elderly population.…”