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01-06-2014 | Review Article

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

Authors: Ye Yuan, Fenglan Niu, Ya Liu, Na Lu

Published in: Neurological Sciences | Issue 6/2014

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.

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

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

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 65:2146–2156PubMedCrossRef

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

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

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

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:e55384PubMedCentralPubMedCrossRef

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

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

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 5:781–788PubMedCrossRef

11.

Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158PubMedCrossRef

12.

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

13.

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

14.

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

15.

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

16.

Bush AI (2013) The metal theory of Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S277–S281PubMed

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 265:1464–1467PubMedCrossRef

18.

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

19.

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

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 77:55–60PubMedCrossRef

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 150:357–369PubMedCrossRef

22.

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

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 269:12152–12158PubMed

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 269:26618–26621PubMed

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 38:9373–9378PubMedCrossRef

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 209-115PubMed

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 62:15–28PubMedCrossRef

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 92:1104–1115PubMedCrossRef

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 10:100–108PubMedCrossRef

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 96:2414–2419PubMedCentralPubMedCrossRef

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 21:4183–4187PubMed

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 46:731–735PubMedCrossRef

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 70:2212–2215PubMedCrossRef

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 29:757–767PubMedCrossRef

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 200:710–715PubMedCrossRef

36.

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

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 91:3270–3274PubMedCentralPubMedCrossRef

38.

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

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 93:2312–2316PubMedCentralPubMedCrossRef

40.

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

41.

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

42.

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

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 21:2973–2990PubMedCentralPubMedCrossRef

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 26:59–68PubMed

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 25:117–123CrossRef

46.

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

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 225:573–580PubMedCentralPubMed

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

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 275:19439–19442PubMedCrossRef

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 272:18530–18533PubMedCrossRef

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 4:327–332PubMed

52.

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

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 78:600–610PubMedCrossRef

54.

Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111PubMed

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 100:6157–6162PubMedCentralPubMedCrossRef

56.

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

57.

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

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:e176PubMedCentralPubMedCrossRef

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 59:43–55PubMedCrossRef

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 30:665–676PubMedCrossRef

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 60:1685–1691PubMedCrossRef

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 29:4004–4015PubMedCrossRef

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 7:779–786PubMedCrossRef

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 20:509–516PubMed

Title: Zinc and its effects on oxidative stress in Alzheimer’s disease
Authors: Ye Yuan
Fenglan Niu
Ya Liu
Na Lu
Publication date: 01-06-2014
Publisher: Springer Milan
Published in: Neurological Sciences / Issue 6/2014
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-014-1668-x

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

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