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Molecular mechanism of zinc neurotoxicity in Alzheimer’s disease

Environmental Science and Pollution Research volume 27, pages 43542–43552 (2020)Cite this article

Abstract

Zinc (Zn) is an essential trace element for most organisms, including human beings. It plays a crucial role in several physiological processes such as catalytic reaction of enzymes, cellular growth, differentiation and metabolism, intracellular signaling, and modulation of nucleic acid structure. Zn containing above 50 metalloenzymes is responsible for proteins, receptors, and hormones synthesis and has a critical role in neurodevelopment. Zn also regulates excitatory and inhibitory neurotransmitters such as glutamate and GABA and is found in high concentration in the synaptic terminals of hippocampal mossy fibers that maintains cognitive function. It regulates LTP and LTD by regulation of AMPA and NMDA receptors. But an excess or deficiency of Zn becomes neurotoxic or cause impairment in growth or sexual maturation. There is mounting evidence that supports this idea of Zn becoming neurotoxic and being involved in the pathogenesis of AD. Zn dyshomeostasis in AD is an area that needs attention as moderate concentration of Zn is involved in the memory regulation via regulation of amyloid plaque. Dyshomeostasis of Zn is involved in the pathogenesis of diseases like AD, ALS, depression, PD, and schizophrenia.

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References

  • Aaseth J, Dusek P, Roos PM (2018) Prevention of progression in Parkinson’s disease. Biometals 31:737–747

    CAS  Google Scholar 

  • Adlard PA, Chung RS (2015) The molecular pathology of cognitive decline: focus on metals. Front Aging Neurosci 7:116

    Google Scholar 

  • Agnihotri A, Aruoma OI (2020) Alzheimer’s disease and parkinson’s disease: a nutritional toxicology perspective of the impact of oxidative stress, mitochondrial dysfunction, nutrigenomics and environmental chemicals. J Am Coll Nutr 39(1):16–27

  • Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease:Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:270–279

    Google Scholar 

  • Al-Saleh I, Nester M, Abduljabbar M, Al-Rouqi R, Eltabache C, Al-Rajudi T, Elkhati R (2016) Mercury (Hg) exposure and its effects on Saudi breastfed infant’s neurodevelopment. Int J Hyg Environ Health 219:129–135

    CAS  Google Scholar 

  • Andrade VM, Aschner M, Marreilha dos Santos AP (2017) Neurotoxicity of metal mixtures. Adv Neurobiol 18:227–265

    CAS  Google Scholar 

  • Bagherani N, Smoller BR (2016) An overview of zinc and its importance in dermatology-part I: Importance and function of zinc in human beings. Glob Dermatol 3:330–336

    Google Scholar 

  • Balachandran RC, Mukhopadhyay S, McBride D, Veevers J, Harrison FE, Aschner M, Haynes EN, Bowman AB (2020) Brain manganese and the balance between essential roles and neurotoxicity. J Biol Chem:1–31

  • Barnham KJ, Bush AI (2008) Metals in Alzheimer’s and Parkinson’s diseases. Curr Opin Chem Biol 12:222–228

    CAS  Google Scholar 

  • Barroso I, Farinha R, Guimarães JT (2018) Proper zinc evaluation in clinical practice: Effect of sample type and its stability. Clin Biochem 59:93–95

    CAS  Google Scholar 

  • Basha R, Wei W, Brydie M, Razmiafshari M, Zawia NH (2003) Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: in vivo evidence for Pb and Zn competition. Int J Dev Neurosci 21:1–12

    CAS  Google Scholar 

  • Bates KA, Verdile G, Li Q-X, Ames D, Hudson P, Masters CL, Martins RN (2009) Clearance mechanisms of Alzheimer’s amyloid-b peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry 14:469–486

    CAS  Google Scholar 

  • Beyer N, Coulson DT, Heggarty S, Ravid R, Hellemans J, Irvine GB, Johnston JA (2012) Zinc Transporter mRNA Levels in Alzheimer’s Disease Postmortem Brain. J Alzheimers Dis 29:863–873

    CAS  Google Scholar 

  • Bonda DJ, Lee H, Blair JA, Zhu X, Perryab G, Smitha MA (2011) Role of metal dyshomeostasis in Alzheimer’s disease. Metallomics 3:267–270

    CAS  Google Scholar 

  • Brown KH, Wuehler SE, Peerson JM (2001) The importance of zinc in human nutrition and estimation of the global prevalence of zinc deficiency. Foo J Alzheimers Dis d Nutr Bull 22:113–125

    Google Scholar 

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

    Google Scholar 

  • Bush A, Pettingell W, Multhaup G, Paradis M, Vonsattel J, Gusella J, Tanzi R (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464–1467

    CAS  Google Scholar 

  • Ceccatelli S, Daréb E, Moors M (2010) Methylmercury-induced neurotoxicity and apoptosis. Chem Biol Interact 188:301–308

    CAS  Google Scholar 

  • Chen T, Zhang Y, Shang Y, Gu X, Zhu Y, Zhu L (2018) NBD-BPEA regulates Zn2+- or Cu2+-induced Aβ40 aggregation and cytotoxicity. Food Chem Toxicol 30:260–267

    Google Scholar 

  • Chiorcea-Paquim A, Enache TA, Oliveira-Brett AM (2018) Electrochemistry of Alzheimer disease amyloid beta peptides. Curr Med Chem 25:4066–4083

    CAS  Google Scholar 

  • Corkins MR (2019) Aluminum effects in infants and children. Pediatrics 144 (6):e20193148

  • Costa LG (1998) Biochemical and molecular neurotoxicology: relevance to biomarker development, neurotoxicity testing and risk assessment. Toxicol Lett 103:417–421

    Google Scholar 

  • Costa LG, Manzo L (1995) Biochemical markers of neurotoxicity: research epidemiological applications. Toxicol Lett 77:137–144

    CAS  Google Scholar 

  • De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV (2012) Alzheimer’s Disease. Subcell Biochem 65:329–352

    CAS  Google Scholar 

  • DeTure MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14:32–36

    Google Scholar 

  • Doneray H, Olcaysu E, Yildirim A, Ozden A (2017) The effect of the zinc concentration in breast milk on neonatal weight gain. J Trace Elem Med Biol 41:32–35

    CAS  Google Scholar 

  • Dong S, Duan Y, Hu Y, Zhao Z (2012) Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis. Transl. Neurodegener12: 1-18

  • Dusek P, Roos PM, Litwin T, Schneider SA, Flaten TP, Aaseth J (2015) The neurotoxicity of iron, copper and manganese in Parkinson’s and Wilson’s diseases. J Trace Elem Med Biol 31:193–203

    CAS  Google Scholar 

  • Ekino S, Susa M, Ninomiya T, Imamura K, Kitamura T (2007) Minamata disease revisited: an update on the acute and chronic manifestations of methyl mercury poisoning. J Neurol Sci 262:131–144

    CAS  Google Scholar 

  • Fallah A, Mohammad-Hasani A, Colagar AH (2018) Zinc is an Essential Element for Male Fertility: A Review of Zn Roles in Men’s Health, Germination, Sperm Quality, and Fertilization. J Reprod Infertil 19:69–81

    Google Scholar 

  • Forsleff L, Schauss AG, Bier ID, Stuart S (1999) Evidence of functional zinc deficiency in Parkinson's disease. J Altern Complement Med 5:57–64

    CAS  Google Scholar 

  • Forte G, Alimonti A, Pino A, Stanzione P, Brescianini S, Brusa L, Sancesario G, Violante N, Bocca B (2005) Metals and oxidative stress in patients with Parkinson's disease. Ann I Super Sanita 41:189–195

    CAS  Google Scholar 

  • Garzon-Rodriguez W, Yatsimirsky AK, Glabe CG (1999) Binding of Zn (II), Cu (II), and Fe (II) ions to alzheimer's Aß peptide studied by fluorescence. Bioorg Med Chem Lett 9:2243–2248

    CAS  Google Scholar 

  • Genoud S, Roberts BR, Gunn AP, Halliday GM, Lewis SJ, Ball HJ, Hare DJ, Double KL (2017) Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain. Metallomics 9:1447–1455

    CAS  Google Scholar 

  • Gower-Winter SD, Levenson CW (2012) Zinc in the central nervous system: From molecules to behaviour. Biofactors 38:186–193

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Hancock SM, Finkelstein DI, Adlard PA (2014) Glia and zinc in ageing and Alzheimer’s disease: a mechanism for cognitive decline? Front Aging Neurosci 6:137–142

    Google Scholar 

  • Hane F, Leonenko Z (2014) Effect of metals on kinetic pathways of amyloid-β aggregation. Biomolecules 4:101–116

    Google Scholar 

  • Harilal S, Jose J, Parambi DG, Kumar R, Mathew GE, Uddin MS, Kim H, Mathew B (2019) Advancements in nanotherapeutics for Alzheimer’s disease: current perspectives. J. Pharm Pharmacol 71:1370–1383

    CAS  Google Scholar 

  • Horgusluoglu E, Nudelman K, Nho K, Saykin AJ (2016) Adult neurogenesis and neurodegenerative diseases: a systems biology perspective. Am J Med Genet B Neuropsychiatr Genet 174:93–112

    Google Scholar 

  • Huang Y, Wu Z, Cao Y, Lang M, Lu B, Zhou B (2014) Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation. Cell Rep 8:831–842

    CAS  Google Scholar 

  • James SA, Churches QI, de Jonge MD, Birchall IE, Streltsov V, McColl G, Adlard PA, Hare DJ (2017) Iron, copper, and zinc concentration in Aβ plaques in the APP/PS1 mouse model of Alzheimer's disease correlates with metal levels in the surrounding neuropil. ACS Chem Neurosci 15:629–637

    Google Scholar 

  • Jellinger KA (2013) The relevance of metals in the pathophysiology of neurodegeneration, pathological considerations. Int Rev Neurobiol 110:1–47

    CAS  Google Scholar 

  • Johnson JW, Kotermanski SE (2006) Mechanism of action of memantine. Curr Opin Pharmacol 6:61–67

    CAS  Google Scholar 

  • Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283:65–87

    CAS  Google Scholar 

  • Jomova K, Vondrakova D, Lawson M, Valko M (2010) Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 345:91–104

    CAS  Google Scholar 

  • Kandiah N, Pai MC, Senanarong V, Looi I, Ampil E, Park KW, Karanam AK, Christopher S (2017) Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia. Clin Interv Aging 12:697–707

    CAS  Google Scholar 

  • Karri V, Schuhmacher M, Kumar V (2016) Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: a general review of metal mixture mechanism in brain. Environ Toxicol Pharmacol 48:203–213

    CAS  Google Scholar 

  • Kausar S, Mustafa HG, Altaf AA, Mustafa G, Badshah A (2019) Galantamine. In: Reference Module in Biomedical Sciences, Netherlands

  • Kim I, Park EJ, Seo J, Ko SJ, Lee J (2011) Zinc stimulates tau S214 phosphorylation by the activation of Raf/mitogen-activated protein kinasekinase/extracellular signal-regulated kinase pathway. Neuroreport 22:839–844

    CAS  Google Scholar 

  • Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67:195–203

    CAS  Google Scholar 

  • Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M (1999) Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc NatlAcadSciUSA 96:3922–3927

    CAS  Google Scholar 

  • Li X, Du X, Ni J (2019) Zn2+ Aggravates tau aggregation and neurotoxicity. Int J Mol Sci 20:487–504

    CAS  Google Scholar 

  • Liu Y, Nguyen M, Robert A, Meunier B (2019a) Metal Ions in Alzheimer’s Disease: A Key Role or Not? Acc Chem Res 52:2026–2035

    CAS  Google Scholar 

  • Liu PP, Xie Y, Meng XY, Kang JS (2019b) History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Tar 4:1–22

    Google Scholar 

  • Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci 158:47–52

    CAS  Google Scholar 

  • Mantyh P, Ghilardi J, Rogers S, DeMaster E, Allen C, Stimson E, Maggio J (1993) Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of B-Amyloid peptide. J Neurochem 61:1171–1174

    CAS  Google Scholar 

  • Méndez-Armenta M, Ríos C (2007) Cadmium neurotoxicity. Environ Toxicol Pharmacol 23:350–358

    Google Scholar 

  • Mezzaroba L, Alfieri DF, Simão ANC, Reiche EMV (2019) The role of zinc, copper, manganese and iron in neurodegenerative diseases. Neurotoxicology 74:230–241

    CAS  Google Scholar 

  • Morris DR, Levenson CW (2017) Neurotoxicity of Zinc. Adv Neurobiol 18:303–312

    Google Scholar 

  • Myhre O, Utkilen H, Duale N, Brunborg G, Hofer T (2013) Metal dyshomeostasis and inflammation in Alzheimer’s and Parkinson’s diseases: possible impact of environmental exposures. Oxidative Med Cell Longev 726954:1–19

    Google Scholar 

  • Pan L, Patterson JC (2013) Molecular dynamics study of Zn (Aβ) And Zn(Aβ)2. PLoS One 8:70681

    Google Scholar 

  • Peters DG, Connor JR, Meadowcroft MD (2015) The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin. Neurobiol Dis 81:49–65

    CAS  Google Scholar 

  • Petrilli MA, Kranz TM, Kleinhaus K, Joe P, Getz M, Johnson P, Chao MV, Malaspina D (2017) The emerging role for zinc in depression and psychosis. Front Pharmacol 8:414

    Google Scholar 

  • Porlas RV, Lynn CL, de Castillo PCC, Dioquino (2018) Neurologic Wilson disease: case series on a diagnostic and therapeutic emergency. Dialogues Clin Neurosci 20(4):341–345

    Google Scholar 

  • Rachakonda V, Pan TH, Le WD (2004) Biomarkers of neurodegenerative disorders: how good are they? Cell Res 14:349–360

    Google Scholar 

  • Roberts BR, Ryan TM, Bush AI, Masters CI, Duce JA (2012) The role of metallobiology and mmyloid-β meptides in alzheimer’s disease. J Neurochem 120:149–166

  • Sanabria-Castro A, Alvarado-Echeverría I, Monge-Bonilla C (2017) Molecular pathogenesis of Alzheimer’s disease: an update. Ann Neurosci 24:46–54

  • Sensi SL, Paoletti P, Bush AI, Sekler I (2009) Zinc in the Physiology and Pathology of the CNS. Nat Rev Neurosci 10:780–791

    CAS  Google Scholar 

  • Siblerud R, Mutter R, Moore E, Naumann J, Walach H (2019) A hypothesis and evidence that mercury may be an etiological factor in Alzheimer's disease. Int J Environ Res Public Health 24:5152–5161

    Google Scholar 

  • Skrajnowska D, Bobrowska-Korczak B (2019) Role of zinc in immune system and anti-cancer defense mechanisms. Nutrients 22:2273–2281

    Google Scholar 

  • Smith AP, Lee NM (2007) Role of zinc in ALS. Amyotroph Lateral Sc 8:131–143

    CAS  Google Scholar 

  • Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer's disease amyloid β peptide. Biochim Biophys Acta 1768:1976–1990

    CAS  Google Scholar 

  • Sun X, Wei Y, Xiong Y, Wang X, Xie A, Wang X, Yang Y, Wang Q, Lu Y, Liu R, Wang J (2012) Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A). J Biol Chem 287:11174–11182

    CAS  Google Scholar 

  • Sung P, Lin P, Liu C, Su H, Tsai K (2020) Neuroinflammation and neurogenesis in Alzheimer's disease and potential therapeutic approaches. Int J Mol Sci 21:701

    CAS  Google Scholar 

  • Swerdlow RH (2007) Pathogenesis of Alzheimer’s disease. Clin Interv Aging 2:347–359

    CAS  Google Scholar 

  • Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5:33

    Google Scholar 

  • Tarohda T, Ishida Y, Kawai K, Yamamoto M, Amano R (2005) Regional distributions of manganese, iron, copper, and zinc in the brains of 6-hydroxydopamine-induced parkinsonian rats. Anal Bioanal Chem 383:224–234

    CAS  Google Scholar 

  • Tewari D, Stankiewicz AM, Mocan A, Sah AN, Tzvetkov NT, Huminiecki L, Horbańczuk JO, Atanasov AG (2018) Ethnopharmacological approaches for dementia therapy and significance of natural products and herbal drugs. Front Aging Neurosci 10:3

    Google Scholar 

  • Thakur AK, Kamboj P, Goswami K, Ahuja K (2018) Pathophysiology and management of alzheimer’s disease: an overview. J anal pharm Res 9:226–235

    Google Scholar 

  • Tyszka-Czochara M, Grzywacz A, Gdula-Argasi J, Librowski T, Wili-Ski B, Opoka W (2014) The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function. Acta Pol Pharm 71:369–377

    Google Scholar 

  • Valko M, Morris H, Cronin MTD (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208

    CAS  Google Scholar 

  • Wang C, Wang T, Zheng W, Zhao B, Danscher G, Chen Y, Wang Z (2010) Zinc overload enhances APP cleavage and Aβ deposition in the Alzheimer mouse brain. PLoS One 12:15349–15355

    Google Scholar 

  • Wang L, Yin YL, Liu XZ, Shen P, Zheng YG, Lan XR, Lu CB, Wang JZ (2020) Current understanding of metal ions in the pathogenesis of Alzheimer’s disease. Transl Neurodegener 9:1–13

    Google Scholar 

  • Watt NT, Whitehouse IJ, Hooper NM (2011) The role of zinc in Alzheimer's disease. Int J Alzheimers Dis 2011:1–10

    Google Scholar 

  • Wright RO, Baccarelli A (2007) Metals and neurotoxicology. J Nutr 137:2809–2813

    CAS  Google Scholar 

  • Yamasaki T, Muranaka H, Kaseda Y, Mimori Y, Tobimatsu S (2012) Understanding the pathophysiology of Alzheimer's disease and mild cognitive impairment: a mini review on fMRI and ERP studies. Neurol Res Int 719056:1–10

    Google Scholar 

  • Yokel RA (2006) Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. J Alzheimers Dis 10:223–253

    Google Scholar 

  • Zatta P, Drago D, Bolognin S, Sensi SL (2009) Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol Sci 30:346–355

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Affiliations

  1. P.G. Department of Pharmacology, College of Pharmaceutical Sciences, Govt. Medical College, Kannur, 670503, India

    Siju Ellickal Narayanan & Anju Vincent

  2. Department of Pharmaceutical Chemistry, Dr. Joseph Mar Thoma Institute of Pharmaceutical Sciences & Research, Kayamkulam, Kerala, 690503, India

    Nisha Abdul Rehuman

  3. Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India

    Seetha Harilal

  4. College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode, 673008, India

    Rajalakshmi Ganesan Rajamma

  5. Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

    Tapan Behl

  6. Department of Pharmacy, Southeast University, Dhaka, Bangladesh

    Md. Sahab Uddin

  7. Pharmakon Neuroscience Research Network, Dhaka, Bangladesh

    Md. Sahab Uddin

  8. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  9. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  10. Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala, 678557, India

    Bijo Mathew

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  1. Siju Ellickal Narayanan
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Narayanan, S.E., Rehuman, N.A., Harilal, S. et al. Molecular mechanism of zinc neurotoxicity in Alzheimer’s disease. Environ Sci Pollut Res 27, 43542–43552 (2020). https://doi.org/10.1007/s11356-020-10477-w

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Keywords

  • Alzheimer’s disease
  • Zinc dyshomeostasis
  • Neurotoxic
  • Amyloid plaque
  • NMDA receptors
  • Gluzinergic neurons