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Zinc and its effects on oxidative stress in Alzheimer’s disease

Neurological Sciences volume 35, pages 923–928 (2014)Cite this article

Abstract

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disorder. The patho-physiological characteristic of AD is abnormal deposition of fibrillar amyloid β protein, intracellular neurofibrillary tangles, oxidative damage and neuronal death in the brain. Zinc is an important trace element in human body regulating many physiological processes. Increasing evidence suggests that the etiology of AD may involve disruptions of zinc homeostasis, and oxidative stress facilitating reactive oxygen species production is an early and sustained event in AD disease progression. Both Zn deficiency and Zn overload may affect cellular Zn distribution and be linked to neurodegeneration in AD. Meanwhile, Zn may play paradoxical roles in initiating and inhibiting oxidative stress and neurotoxicity. This review will focus on aspects of the role of zinc in AD, which includes a large body of research regarding zinc dyshomeostasis and its relation with oxidative stress.

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References

  1. Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240

    CAS  PubMed  Google Scholar 

  2. Hao Q, Maret W (2005) Imbalance between pro-oxidant and pro-antioxidant functions of zinc in disease. J Alzheimers Dis 8:161–170 discussion 209-115

    CAS  PubMed  Google Scholar 

  3. Hensley K, Hall N, Subramaniam R, Cole P, Harris M et al (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156

    Article  CAS  PubMed  Google Scholar 

  4. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118

    CAS  PubMed  Google Scholar 

  5. Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462

    Article  CAS  PubMed  Google Scholar 

  6. Wyllie AH (1997) Apoptosis: an overview. Br Med Bull 53:451–465

    Article  CAS  PubMed  Google Scholar 

  7. Yang Y, Jing XP, Zhang SP, Gu RX, Tang FX et al (2013) High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling. PLoS One 8:e55384

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Paoletti P, Vergnano AM, Barbour B, Casado M (2009) Zinc at glutamatergic synapses. Neuroscience 158:126–136

    Article  CAS  PubMed  Google Scholar 

  9. Mayer ML, Vyklicky L Jr (1989) The action of zinc on synaptic transmission and neuronal excitability in cultures of mouse hippocampus. J Physiol 415:351–365

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Draguhn A, Verdorn TA, Ewert M, Seeburg PH, Sakmann B (1990) Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+. Neuron 5:781–788

    Article  CAS  PubMed  Google Scholar 

  11. Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158

    Article  PubMed  Google Scholar 

  12. Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781

    Article  CAS  PubMed  Google Scholar 

  13. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    Article  CAS  PubMed  Google Scholar 

  14. Lyubartseva G, Lovell MA (2012) A potential role for zinc alterations in the pathogenesis of Alzheimer’s disease. Biofactors 38:98–106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  16. Bush AI (2013) The metal theory of Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S277–S281

    PubMed  Google Scholar 

  17. Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP et al (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464–1467

    Article  CAS  PubMed  Google Scholar 

  18. Cuajungco MP, Lees GJ (1997) Zinc and Alzheimer’s disease: is there a direct link? Brain Res Brain Res Rev 23:219–236

    Article  CAS  PubMed  Google Scholar 

  19. Cuajungco MP, Lees GJ (1997) Zinc metabolism in the brain: relevance to human neurodegenerative disorders. Neurobiol Dis 4:137–169

    Article  CAS  PubMed  Google Scholar 

  20. Zhang LH, Wang X, Stoltenberg M, Danscher G, Huang L et al (2008) Abundant expression of zinc transporters in the amyloid plaques of Alzheimer’s disease brain. Brain Res Bull 77:55–60

    Article  CAS  PubMed  Google Scholar 

  21. Stoltenberg M, Bush AI, Bach G, Smidt K, Larsen A et al (2007) Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency. Neuroscience 150:357–369

    Article  CAS  PubMed  Google Scholar 

  22. Religa D, Strozyk D, Cherny RA, Volitakis I, Haroutunian V et al (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69–75

    Article  CAS  PubMed  Google Scholar 

  23. Bush AI, Pettingell WH Jr, Paradis MD, Tanzi RE (1994) Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem 269:12152–12158

    CAS  PubMed  Google Scholar 

  24. Bush AI, Pettingell WH Jr, de Paradis M, Tanzi RE, Wasco W (1994) The amyloid beta-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily. J Biol Chem 269:26618–26621

    CAS  PubMed  Google Scholar 

  25. Liu ST, Howlett G, Barrow CJ (1999) Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer’s disease. Biochemistry 38:9373–9378

    Article  CAS  PubMed  Google Scholar 

  26. Capasso M, Jeng JM, Malavolta M, Mocchegiani E, Sensi SL (2005) Zinc dyshomeostasis: a key modulator of neuronal injury. J Alzheimers Dis 8:93–108 discussion 209-115

    CAS  PubMed  Google Scholar 

  27. Zatta P, Lucchini R, van Rensburg SJ, Taylor A (2003) The role of metals in neurodegenerative processes: aluminum, manganese, and zinc. Brain Res Bull 62:15–28

    Article  CAS  PubMed  Google Scholar 

  28. An WL, Bjorkdahl C, Liu R, Cowburn RF, Winblad B et al (2005) Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3β in SH-SY5Y neuroblastoma cells. J Neurochem 92:1104–1115

    Article  CAS  PubMed  Google Scholar 

  29. Sensi SL, Ton-That D, Weiss JH (2002) Mitochondrial sequestration and Ca(2+)-dependent release of cytosolic Zn(2+) loads in cortical neurons. Neurobiol Dis 10:100–108

    Article  CAS  PubMed  Google Scholar 

  30. Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH (1999) Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc Natl Acad Sci USA 96:2414–2419

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187

    CAS  PubMed  Google Scholar 

  32. Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF et al (1998) Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine. J Histochem Cytochem 46:731–735

    Article  CAS  PubMed  Google Scholar 

  33. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL et al (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215

    Article  CAS  PubMed  Google Scholar 

  34. Maynard CJ, Cappai R, Volitakis I, Laughton KM, Masters CL et al (2009) Chronic exposure to high levels of zinc or copper has little effect on brain metal homeostasis or Abeta accumulation in transgenic APP-C100 mice. Cell Mol Neurobiol 29:757–767

    Article  CAS  PubMed  Google Scholar 

  35. Butterfield DA, Hensley K, Harris M, Mattson M, Carney J (1994) Beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem Biophys Res Commun 200:710–715

    Article  CAS  PubMed  Google Scholar 

  36. Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817–827

    Article  CAS  PubMed  Google Scholar 

  37. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M et al (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91:3270–3274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171

    Article  CAS  PubMed  Google Scholar 

  39. Bruce AJ, Malfroy B, Baudry M (1996) beta-Amyloid toxicity in organotypic hippocampal cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. Proc Natl Acad Sci USA 93:2312–2316

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505

    Article  CAS  PubMed  Google Scholar 

  41. Bareggi SR, Cornelli U (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 18:41–46

    Article  CAS  PubMed  Google Scholar 

  42. Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int 62:540–555

    Article  CAS  PubMed  Google Scholar 

  43. Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP et al (2012) Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer’s disease: implications for neuroprotection and lifespan extension. Hum Mol Genet 21:2973–2990

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM et al (2011) Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 26:59–68

    CAS  PubMed  Google Scholar 

  45. Vina J, Lloret A, Orti R, Alonso D (2004) Molecular bases of the treatment of Alzheimer’s disease with antioxidants: prevention of oxidative stress. Mol Asp Med 25:117–123

    Article  CAS  Google Scholar 

  46. Powell SR (2000) The antioxidant properties of zinc. J Nutr 130:1447S–1454S

    CAS  PubMed  Google Scholar 

  47. Gibbs PN, Gore MG, Jordan PM (1985) Investigation of the effect of metal ions on the reactivity of thiol groups in human 5-aminolaevulinate dehydratase. Biochem J 225:573–580

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Da Silva JJR (1991) Zinc: Lewis acid catalysis and regulation. In: Williams RJ (ed) The Biological Chemistry of the Elements. Clarendon Press, Oxford, pp 299–318

    Google Scholar 

  49. Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT et al (2000) Evidence that the beta-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 275:19439–19442

    Article  CAS  PubMed  Google Scholar 

  50. Perry DK, Smyth MJ, Stennicke HR, Salvesen GS, Duriez P et al (1997) Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis. J Biol Chem 272:18530–18533

    Article  CAS  PubMed  Google Scholar 

  51. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 4:327–332

    CAS  PubMed  Google Scholar 

  52. Sensi SL, Yin HZ, Weiss JH (1999) Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production. Neuroreport 10:1723–1727

    Article  CAS  PubMed  Google Scholar 

  53. Seo SR, Chong SA, Lee SI, Sung JY, Ahn YS et al (2001) Zn2+ -induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells. J Neurochem 78:600–610

    Article  CAS  PubMed  Google Scholar 

  54. Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111

    CAS  PubMed  Google Scholar 

  55. Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR et al (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc Natl Acad Sci USA 100:6157–6162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD (2001) The role of zinc in caspase activation and apoptotic cell death. Biometals 14:315–330

    Article  CAS  PubMed  Google Scholar 

  57. Dineley KE, Votyakova TV, Reynolds IJ (2003) Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem 85:563–570

    Article  CAS  PubMed  Google Scholar 

  58. Corona C, Pensalfini A, Frazzini V, Sensi SL (2011) New therapeutic targets in Alzheimer’s disease: brain deregulation of calcium and zinc. Cell Death Dis 2:e176

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E et al (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59:43–55

    Article  CAS  PubMed  Google Scholar 

  60. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD et al (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676

    Article  CAS  PubMed  Google Scholar 

  61. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691

    Article  PubMed  Google Scholar 

  62. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004–4015

    Article  CAS  PubMed  Google Scholar 

  63. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7:779–786

    Article  CAS  PubMed  Google Scholar 

  64. Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A et al (2010) PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 20:509–516

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Department of Anesthesiology, The First Bethune Hospital of Jilin University, Changchun, People’s Republic of China

    Ye Yuan

  2. The School of Public Health, Jilin University, Changchun, People’s Republic of China

    Fenglan Niu & Ya Liu

  3. The Department of Pediatrics, The First Bethune Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, 130021, People’s Republic of China

    Na Lu

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  1. Ye Yuan
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  2. Fenglan Niu
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  3. Ya Liu
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Correspondence to Na Lu.

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Yuan, Y., Niu, F., Liu, Y. et al. Zinc and its effects on oxidative stress in Alzheimer’s disease. Neurol Sci 35, 923–928 (2014). https://doi.org/10.1007/s10072-014-1668-x

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