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Neurotoxicity of Zinc

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Neurotoxicity of Metals

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 18))

Abstract

Zinc-induced neurotoxicity has been shown to play a role in neuronal damage and death associated with traumatic brain injury, stroke, seizures, and neurodegenerative diseases. During normal firing of “zinc-ergic” neurons, vesicular free zinc is released into the synaptic cleft where it modulates a number of postsynaptic neuronal receptors. However, excess zinc, released after injury or disease, leads to excitotoxic neuronal death. The mechanisms of zinc-mediated neurotoxicity appear to include not only neuronal signaling but also regulation of mitochondrial function and energy production, as well as other mechanisms such as aggregation of amyloid beta peptides in Alzheimer’s disease. However, recent data have raised questions about some of our long-standing assumptions about the mechanisms of zinc in neurotoxicity. Thus, this review explores the most recent published findings and highlights the current mechanistic controversies.

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References

  • Abelein A, Gräslund A, Danielsson J. Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation. Proc Natl Acad Sci U S A. 2015;112:5407–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abramovitch-Dahan C, Asraf H, Bogdanovic M et al. Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+ , ERK1/2 and Clusterin signaling in neurons. J Neurochem. 2016. doi:10.1111/jnc.13760.

  • Anderson CT, Radford RJ, Zastrow ML, et al. Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc. Proc Natl Acad Sci U S A. 2015;112:E2705–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellou V, Belbasis L, Tzoulaki I, et al. Systematic evaluation of the associations between environmental risk factors and dementia: an umbrella review of systematic reviews and meta-analyses. Alzheimers Dement pii. 2016;S1552-5260(16):32853–9.

    Google Scholar 

  • Bush AI. The metal theory of Alzheimer’s disease. J Alzheimers Dis. 2013;33(Suppl 1):S277–81.

    PubMed  Google Scholar 

  • Cai AL, Zipfel GJ, Sheline CT. Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway. Eur J Neurosci. 2006;24:2169–76.

    Article  PubMed  Google Scholar 

  • Cope EC, Morris DR, Scrimgeour AG, et al. Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury. Physiol Behav. 2011;104:942–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cope EC, Morris DR, Gower-Winter SD, et al. Effect of zinc supplementation on neuronal precursor proliferation in the rat hippocampus after traumatic brain injury. Exp Neurol. 2016;279:96–103.

    Article  CAS  PubMed  Google Scholar 

  • Corona C, Pensalfini A, Frazzini V, et al. New therapeutic targets in Alzheimer’s disease: brain deregulation of calcium and zinc. Cell Death Dis. 2011;2:e176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dineley KE, Votyakova TV, Reynolds IJ. Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem. 2003;85:563–70.

    Article  CAS  PubMed  Google Scholar 

  • Eom JW, Lee JM, Koh JY, et al. AMP-activated protein kinase contributes to zinc-induced neuronal death via activation by LKB1 and induction of Bim in mouse cortical cultures. Mol Brain. 2016;9:14.

    Article  PubMed  PubMed Central  Google Scholar 

  • Floriańczyk B, Trojanowski T. Inhibition of respiratory processes by overabundance of zinc in neuronal cells. Folia Neuropathol. 2009;47:234–9.

    PubMed  Google Scholar 

  • Garai K, Sahoo B, Kaushalya SK, et al. Zinc lowers amyloid-beta toxicity by selectively precipitating aggregation intermediates. Biochemistry. 2007;46:10655–63.

    Article  CAS  PubMed  Google Scholar 

  • Granzotto A, Sensi SL. Intracellular zinc is a critical intermediate in the excitotoxic cascade. Neurobiol Dis. 2015;81:25–37.

    Article  CAS  PubMed  Google Scholar 

  • Greenough MA, Camakaris J, Bush AI. Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int. 2013;62:540–55.

    Article  CAS  PubMed  Google Scholar 

  • Hancock SM, Finkelstein DI, Adlard PA. Glia and zinc in ageing and Alzheimer’s disease: a mechanism for cognitive decline? Front Aging Neurosci. 2014;6:137.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hane FT, Hayes R, Lee BY, et al. Effect of copper and zinc on the single molecule self-affinity of Alzheimer’s amyloid-β peptides. PLoS One. 2016;11:e0147488.

    Article  PubMed  PubMed Central  Google Scholar 

  • He K, Aizenman E. ERK signaling leads to mitochondrial dysfunction in extracellular zinc-induced neurotoxicity. J Neurochem. 2010;114:452–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosie AM, Dunne EL, Harvey RJ, et al. Zinc-mediated inhibition of GABA(a) receptors: discrete binding sites underlie subtype specificity. Nat Neurosci. 2003;6:362–9.

    Article  CAS  PubMed  Google Scholar 

  • Inoue K, O’Bryant Z, Xiong ZG. Zinc-permeable ion channels: effects on intracellular zinc dynamics and potential physiological/pathophysiological significance. Curr Med Chem. 2015;22:1248–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Istrate AN, Kozin SA, Zhokhov SS, et al. Interplay of histidine residues of the Alzheimer’s disease Aβ peptide governs its Zn-induced oligomerization. Sci Rep. 2016;6:21734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan MZ. A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy. Biomed Pharmacother. 2016;79:263–72.

    Article  CAS  PubMed  Google Scholar 

  • Khmeleva SA, Radko SP, Kozin SA, et al. Zinc-mediated binding of nucleic acids to amyloid-β aggregates: role of histidine residues. J Alzheimers Dis. 2016;54:809–19.

    Article  CAS  PubMed  Google Scholar 

  • Kim SW, Lee HK, Kim HJ, et al. Neuroprotective effect of ethyl pyruvate against Zn(2+) toxicity via NAD replenishment and direct Zn(2+) chelation. Neuropharmacology. 2016a;105:411–9.

    Article  CAS  PubMed  Google Scholar 

  • Kim Y, Oh HG, Cho YY, et al. Stress hormone potentiates Zn(2+)-induced neurotoxicity via TRPM7 channel in dopaminergic neuron. Biochem Biophys Res Commun. 2016b;470:362–7.

    Article  CAS  PubMed  Google Scholar 

  • Klein HU, Bennett DA, De Jager PL. The epigenome in Alzheimer’s disease: current state and approaches for a new path to gene discovery and understanding disease mechanism. Acta Neuropathol. 2016;132:503–14.

    Article  CAS  PubMed  Google Scholar 

  • Kuenzel K, Friedrich O, Gilbert DF. A recombinant human pluripotent stem cell line stably expressing halide-sensitive YFP-I152L for GABAAR and GlyR-targeted high-throughput drug screening and toxicity testing. Front Mol Neurosci. 2016;9:51.

    Article  PubMed  PubMed Central  Google Scholar 

  • Leng TD, Lin J, Sun HW, et al. Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity. CNS Neurosci Ther. 2015;21:32–9.

    Article  CAS  PubMed  Google Scholar 

  • Lovelle MA, Robertson JD, Teesdale WJ, et al. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol Sci. 1998;158:47–52.

    Article  Google Scholar 

  • Matheou CJ, Younan ND, Viles JH. The rapid exchange of zinc(2+) enables trace levels to profoundly influence amyloid-β Misfolding and dominates assembly outcomes in cu(2+)/Zn(2+) mixtures. J Mol Biol. 2016;428:2832–46.

    Article  CAS  PubMed  Google Scholar 

  • Mezentsev YV, Medvedev AE, Kechko OI, et al. Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer’s disease? J Biomol Struct Dyn. 2016;21:1–10.

    Google Scholar 

  • Morris DR, Levenson CW. Ion channels and zinc: mechanisms of neurotoxicity and neurodegeneration. J Toxicol. 2012;2012:785647.

    Article  PubMed  PubMed Central  Google Scholar 

  • Panahpour H, Nekooeian AA, Dehghani GA. Blockade of central angiotensin II AT1 receptor protects the brain from ischemia/reperfusion injury in normotensive rats. Iran J Med Sci. 2014;39:536–42.

    PubMed  PubMed Central  Google Scholar 

  • Park MH, Kim HN, Lim JS, et al. Angiotensin II potentiates zinc-induced cortical neuronal death by acting on angiotensin II type 2 receptor. Mol Brain. 2013;6:50.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pivovarova NB, Stanika RI, Kazanina G, et al. The interactive roles of zinc and calcium in mitochondrial dysfunction and neurodegeneration. J Neurochem. 2014;128:592–602.

    Article  CAS  PubMed  Google Scholar 

  • Poddar R, Rajagopal S, Shuttleworth CW, et al. Zn2+−dependent activation of the Trk signaling pathway induces phosphorylation of the brain-enriched tyrosine phosphatase STEP: MOLECULAR BASIS FOR ZN2+−INDUCED ERK MAPK ACTIVATION. J Biol Chem. 2016;291:813–25.

    Article  CAS  PubMed  Google Scholar 

  • Sensi S. Metal homeostasis in dementia. Free Radic Biol Med. 2014;75(Suppl 1):S9.

    Google Scholar 

  • Seo BR, Lee SJ, Cho KS, et al. The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells. Neurobiol Aging. 2015;36:3228–38.

    Article  CAS  PubMed  Google Scholar 

  • Serraz B, Grand T, Paoletti P. Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations. Neuropharmacology. 2016;109:196–204.

    Article  CAS  PubMed  Google Scholar 

  • Sharma AK, Pavlova ST, Kim J, et al. The effect of cu(2+) and Zn(2+) on the Aβ42 peptide aggregation and cellular toxicity. Metallomics. 2013;5:1529–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheline CT, Cai AL, Zhu J, et al. Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+. Eur J Neurosci. 2010;32:894–904.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shi H, Wang HL, Pu HJ, et al. Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury. CNS Neurosci Ther. 2015;21:374–84.

    Article  CAS  PubMed  Google Scholar 

  • Smart TG, Moss SJ, Xie X, et al. GABAA receptors are differentially sensitive to zinc: dependence on subunit composition. Br J Pharmacol. 1991;103:1837–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeda A, Tamano H. Innervation from the entorhinal cortex to the dentate gyrus and the vulnerability to Zn2. J trace Elem med Biol 2016. pii:S0946-672X(16)30076-1.

    Google Scholar 

  • Turkmen S, Cekic Gonenc O, Karaca Y, et al. The effect of ethyl pyruvate and N-acetylcysteine on ischemia-reperfusion injury in an experimental model of ischemic stroke. Am J Emerg Med. 2016;34:1804–7.

    Article  PubMed  Google Scholar 

  • Uchoa MF, Moser VA, Pike CJ. Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol pii. 2016;S0091-3022(16):30039–5.

    Google Scholar 

  • Villapol S, Balarezo MG, Affram K, et al. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain. 2015;138:3299–315.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang G, Yu X, Wang D, et al. Altered levels of zinc and N-methyl-D-aspartic acid receptor underlying multiple organ dysfunctions after severe trauma. Med Sci Monit. 2015;21:2613–20.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu L, Shan S, Chen Y, et al. Coupling of zinc-binding and secondary structure in Nonfibrillar Aβ40 peptide Oligomerization. J Chem Inf Model. 2015;55:1218–30.

    Article  CAS  PubMed  Google Scholar 

  • Young B, Ott L, Kasarskis E, et al. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma. 1996;13:25–34.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Sciences, The Florida State University College of Medicine, Tallahassee, FL, 32306-4300, USA

    Deborah R. Morris & Cathy W. Levenson

  2. Program in Neuroscience, The Florida State University College of Medicine, Tallahassee, FL, 32306-4300, USA

    Cathy W. Levenson

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  1. Deborah R. Morris
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  2. Cathy W. Levenson
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Correspondence to Cathy W. Levenson .

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Editors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Michael Aschner

  2. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA

    Lucio G. Costa

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Morris, D.R., Levenson, C.W. (2017). Neurotoxicity of Zinc. In: Aschner, M., Costa, L. (eds) Neurotoxicity of Metals. Advances in Neurobiology, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-60189-2_15

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