Crosstalk of Copper and Zinc in the Pathogenesis of Vascular Dementia

Overview

Journal J Clin Biochem Nutr

Specialty Biochemistry

Date 2022 Jul 29

PMID 35903609

Authors

Masahiro Kawahara

Ken-Ichiro Tanaka

Midori Kato-Negishi

Affiliations

Soon will be listed here.

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.

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References

Hartwig C, Mendez G, Bhattacharjee S, Vrailas-Mortimer A, Zlatic S, Freeman A . Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content. J Neurosci. 2020; 41(2):215-233. PMC: 7810662. DOI: 10.1523/JNEUROSCI.1284-20.2020. View

Singh A, Haldar S, Horback K, Tom C, Zhou L, Meyerson H . Prion protein regulates iron transport by functioning as a ferrireductase. J Alzheimers Dis. 2013; 35(3):541-52. PMC: 5450724. DOI: 10.3233/JAD-130218. View

Calderone A, Jover T, Mashiko T, Noh K, Tanaka H, Bennett M . Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death. J Neurosci. 2004; 24(44):9903-13. PMC: 6730239. DOI: 10.1523/JNEUROSCI.1713-04.2004. View

Moons R, Konijnenberg A, Mensch C, Van Elzen R, Johannessen C, Maudsley S . Metal ions shape α-synuclein. Sci Rep. 2020; 10(1):16293. PMC: 7529799. DOI: 10.1038/s41598-020-73207-9. View

Wong B, Tsatsanis A, Lim L, Adlard P, Bush A, Duce J . β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One. 2014; 9(12):e114174. PMC: 4252103. DOI: 10.1371/journal.pone.0114174. View

Chuang S, Reddy D . Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus. Neuropharmacology. 2018; 148:244-256. PMC: 6424640. DOI: 10.1016/j.neuropharm.2018.11.031. View

Subramanian Vignesh K, Deepe Jr G . Metallothioneins: Emerging Modulators in Immunity and Infection. Int J Mol Sci. 2017; 18(10). PMC: 5666878. DOI: 10.3390/ijms18102197. View

Scheiber I, Mercer J, Dringen R . Metabolism and functions of copper in brain. Prog Neurobiol. 2014; 116:33-57. DOI: 10.1016/j.pneurobio.2014.01.002. View

Roman G . Vascular dementia prevention: a risk factor analysis. Cerebrovasc Dis. 2005; 20 Suppl 2:91-100. DOI: 10.1159/000089361. View

10.

Suh S, Silva D, Frederickson C, Thompson R . Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr. 2000; 130(5S Suppl):1471S-83S. DOI: 10.1093/jn/130.5.1471S. View

11.

Vogt K, Mellor J, Tong G, Nicoll R . The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron. 2000; 26(1):187-96. DOI: 10.1016/s0896-6273(00)81149-6. View

12.

Tanaka K, Kasai M, Shimoda M, Shimizu A, Kubota M, Kawahara M . Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response. Oxid Med Cell Longev. 2019; 2019:9693726. PMC: 6604344. DOI: 10.1155/2019/9693726. View

13.

Tang J, Zhuo Y, Li Y . Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury. Front Cell Dev Biol. 2021; 9:720288. PMC: 8383321. DOI: 10.3389/fcell.2021.720288. View

14.

Kawahara M, Kato-Negishi M, Kuroda Y . Pyruvate blocks zinc-induced neurotoxicity in immortalized hypothalamic neurons. Cell Mol Neurobiol. 2002; 22(1):87-93. PMC: 11533741. DOI: 10.1023/a:1015345813075. View

15.

Watt N, Griffiths H, Hooper N . Neuronal zinc regulation and the prion protein. Prion. 2013; 7(3):203-8. PMC: 3783104. DOI: 10.4161/pri.24503. View

16.

Lee J, Kim Y, Koh J . Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci. 2001; 21(20):RC171. PMC: 6763857. View

17.

Sheline C, Behrens M, Choi D . Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. J Neurosci. 2000; 20(9):3139-46. PMC: 6773145. View

18.

Tanaka K, Shimoda M, Chuang V, Nishida K, Kawahara M, Ishida T . Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity. Int J Pharm. 2017; 535(1-2):140-147. DOI: 10.1016/j.ijpharm.2017.11.012. View

19.

Pochwat B, Nowak G, Szewczyk B . Relationship between Zinc (Zn (2+) ) and Glutamate Receptors in the Processes Underlying Neurodegeneration. Neural Plast. 2015; 2015:591563. PMC: 4461779. DOI: 10.1155/2015/591563. View

20.

Black S, Stys P, Zamponi G, Tsutsui S . Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity. Front Cell Dev Biol. 2014; 2:45. PMC: 4207032. DOI: 10.3389/fcell.2014.00045. View