Methylmercury and Alzheimer’s Disease

  • Shabnum Nabi


Methylmercury, a pollutant produced by various industrial activities, is a potent neurotoxin that has now caused serious contamination issues within our oceans. As a fat-soluble molecule, methylmercury enters the food chain and accumulates in the flesh of the fish that then may end up in our supermarkets. Consuming larger, longer living fish on a regular basis is now known to pose a serious health hazard, especially for children and pregnant women who are consequently advised to limit (or even avoid) the intake of some species such as fresh tuna or marlin.


Glutamine Synthetase Mercury Concentration Neurofibrillary Tangle Inorganic Mercury Dental Amalgam 


  1. Allen JW, Mutkus LA, Aschner M (2001) Mercuric chloride, but not methylmercury, inhibits glutamine synthetase activity in primary cultures of cortical astrocytes. Brain Res 891:148–157PubMedCrossRefGoogle Scholar
  2. Arendt Th (2002) Neuronale pathologie. In: Beyreuther K, Einhäupl KM, Förstl H, Kurz A (eds) Demenzen. Thieme, Stuttgart, pp 106–117Google Scholar
  3. Aschner M, Yao CP, Allen JW, Tan KH (2000) Methylmercury alters glutamate transport in astrocytes. Neurochem Int 37:188–206CrossRefGoogle Scholar
  4. Basun H, Forssell LG, Wetterberg L, Winblad B (1991) Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer’s disease. J Neural Transm [P-D Sect] 3:231–258Google Scholar
  5. Bleich S, Romer K, Wiltfang J, Kornhuber J (2003) Glutamate and the glutamate receptor system: a target for drug action. Int J Geriatr Psychiatry 18:S33–S40PubMedCrossRefGoogle Scholar
  6. Braak H, Braak E, Yilmazer D, Bohl J (1995) Age-related changes of the human cerebral cortex. In: Cruz-Sanchez FF, Ravid R, Cuzner ML (eds) Neuropathological diagnostic criteria for brain banking. Biomedical Health Research IOS Press, Amsterdam, pp 14–19Google Scholar
  7. Braak H, Griffing K, Braak E (1997) Neuroanatomy of Alzheimer’s disease. Alzheimer’s Res 3:235–247Google Scholar
  8. Braak E, Griffing K, Arai K, Bohl J, Bratzke H, Braak H (1999) Neuropathology of Alzheimer’s disease: what is new since A. Alzheimer? Eur Arch Psychiatry Clin Neurosci 249:14–22PubMedCrossRefGoogle Scholar
  9. Braak H, Del Tredici K, Schultz C, Braak E (2000) Vulnerability of select neuronal types to Alzheimer’s disease. Ann N Y Acad Sci 924:53–61PubMedCrossRefGoogle Scholar
  10. Breteler MM, Claus JJ, van Duijn CM, Launer LJ, Hofman A (1992) Epidemiology of Alzheimer’s. Epidemiol Rev 14:59–82PubMedGoogle Scholar
  11. Brookes N (1992) In vitro evidence for the role of glutamate in the CNS toxicity of mercury. Toxicology 76:245–256PubMedCrossRefGoogle Scholar
  12. Brookmeyer R, Gray S (2000) Methods for projecting the incidence and prevalence of chronic diseases in aging populations: application to Alzheimer’s. Stat Med 19:1481–1493PubMedCrossRefGoogle Scholar
  13. Bush AI (2002) Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging 23:1031–1038PubMedCrossRefGoogle Scholar
  14. Bush AI (2003a) Copper, zinc, and the metallobiology of Alzheimer’s disease. Alzheimer Dis Assoc Disord 17:147–150PubMedCrossRefGoogle Scholar
  15. Bush AI (2003b) The metallobiology of Alzheimer’s disease. Trends Neurosci 26:207–214PubMedCrossRefGoogle Scholar
  16. Butterfield DA (2002) Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36:1307–1313PubMedCrossRefGoogle Scholar
  17. Butterfield DA, Hensley K, Cole P et al (1997) Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer’s disease. J Neurochem 68:2451–2457PubMedCrossRefGoogle Scholar
  18. Cedrola S, Guzzi G, Ferrari D et al (2003) Inorganic mercury changes the fate of murine CNS stem cells. FASEB J 17:869–871PubMedGoogle Scholar
  19. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55:1449–1455PubMedCrossRefGoogle Scholar
  20. Clarkson TW, Magos L, Myers GJ (2003) The toxicology of mercury-current exposures and clinical manifestations. N Engl J Med 349:1731–1737PubMedCrossRefGoogle Scholar
  21. Cornett CR, Markesbery WR, Ehmann WD (1998) Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain. Neurotoxicology 19:339–346PubMedGoogle Scholar
  22. Crapper McLachlan DR, Dalton AJ, Kruck TP et al (1991) Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 337:1304–1308PubMedCrossRefGoogle Scholar
  23. David S, Shoemaker M, Haley BE (1998) Abnormal properties of creatine kinase in Alzheimer’s disease brain: correlation of reduced enzyme activity and active site photolabeling with aberrant cytosol-membrane partitioning. Brain Res Mol Brain Res 54:276–287PubMedCrossRefGoogle Scholar
  24. Dickson DW (2001) Neuropathology of Alzheimer’s disease and other dementias. Clin Geriatr Med 17:209–228PubMedCrossRefGoogle Scholar
  25. Dickson DW, Crystal HA, Mattiace LA et al (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189PubMedCrossRefGoogle Scholar
  26. Donix M, Poettrich K, Weiss PH, Werner A, von Kummer R, Fink GR, Holthoff VA (2010) Age-dependent differences in the neural mechanisms supporting long-term declarative memories. Arch Clin Neuropsychol 25:383–395PubMedCrossRefGoogle Scholar
  27. Drasch G, Schupp I, Riedl G, Günther G (1992) Einfluß von Amalgamfüllungen auf die Quecksilberkonzentration in menschlichen Organen. Dtsch Zahnarztl Z 47:490–496Google Scholar
  28. Drasch G, Schupp I, Hofl H, Reinke R, Roider G (1994) Mercury burden of human fetal and infant tissues. Eur J Pediatr 153:607–610PubMedCrossRefGoogle Scholar
  29. Drasch G, der Mail S, Schlosser C, Roider G (2000) Content of non-mercury-associated selenium in human tissues. Biol Trace Elem Res 77:219–230PubMedCrossRefGoogle Scholar
  30. Duhr EF, Pendergrass JC, Slevin JT, Haley BE (1993) HgEDTA complex inhibits GTP interactions with the E-site of brain beta-tubulin. Toxicol Appl Pharmacol 122:273–280PubMedCrossRefGoogle Scholar
  31. Eggleston DW, Nylander M (1987) Correlation of dental amalgam with mercury in brain tissue. J Prosthet Dent 58:704–707PubMedCrossRefGoogle Scholar
  32. Ehmann WD, Markesbery WR, Alauddin M, Hossain TI, Brubaker EH (1986) Brain trace elements in Alzheimer’s disease. Neurotoxicology 7:195–206PubMedGoogle Scholar
  33. Ernst RL, Hay JW (1997) Economic research on Alzheimer disease: a review of the Alzheimer. Dis Assoc Disord 11(Suppl 6):135–145Google Scholar
  34. Falconer MM, Vaillant A, Reuhl KR, Laferriere N, Brown DL (1994) The molecular basis of microtubule stability in neurons. Neurotoxicology 15:109–122PubMedGoogle Scholar
  35. Fung YK, Meade AG, Rack EP et al (1995) Determination of blood mercury concentrations in Alzheimer’s patients. J Toxicol Clin Toxicol 33:243–247PubMedCrossRefGoogle Scholar
  36. Fung YK, Meade AG, Rack EP, Blotcky AJ (1997) Brain mercury in neurodegenerative disorders. J Toxicol Clin Toxicol 35:49–54PubMedCrossRefGoogle Scholar
  37. Grant WB (1997) Dietary Links to Alzheimer’s disease. Alzheimer’s Disease Review 2:42–55Google Scholar
  38. Grant WB (1999) Dietary links to Alzheimer’s disease: 1999 update. J Alzheimer’s Dis 1:197–201Google Scholar
  39. Grant WB, Campbell A, Itzhaki RF, Savory J (2002) The significance of environmental factors in the etiology of Alzheimer’s disease. J Alzheimers Dis 4:179–189PubMedGoogle Scholar
  40. Gunnersen D, Haley B (1992) Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker. Proc Natl Acad Sci U S A 89:11949–11953PubMedCentralPubMedCrossRefGoogle Scholar
  41. Guzzi G, Grandi M, Cattaneo C (2002) Should amalgam fillings be removed? Lancet 360:2081PubMedCrossRefGoogle Scholar
  42. Haley B (2002) The relationship of toxic effects of mercury to exacerbation of the medical condition classified as Alzheimer’s disease. Accessed 16 May 2004
  43. Harris HH, Pickering IJ, George GN (2003) The chemical form of mercury in fish. Science 301:1203PubMedCrossRefGoogle Scholar
  44. Helmuth L (2002) New therapies. New Alzheimer’s treatments that may ease the mind. Science 297:1260–1262PubMedCrossRefGoogle Scholar
  45. Helmuth L (2003) Detangling Alzheimer’s disease. New insights into the biological bases of the most common cause of dementia are pointing to better diagnostics and possible therapeutics. Sci Aging Knowledge Environ 2003:oa2Google Scholar
  46. Henderson VW (2000) Oestrogens and dementia. Novartis Found Symp 230:254–265PubMedCrossRefGoogle Scholar
  47. Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 51:896–900PubMedCrossRefGoogle Scholar
  48. Hendrie HC, Osuntokun BO, Hall KS et al (1995) Prevalence of Alzheimer’s disease and dementia in two communities: Nigerian Africans and African Americans. Am J Psychiatry 152:1485–1492PubMedGoogle Scholar
  49. Jellinger KA (2003) General aspects of neurodegeneration. J Neural Transm Suppl 65:101–144PubMedCrossRefGoogle Scholar
  50. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM (1997) Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 42:776–782PubMedCrossRefGoogle Scholar
  51. Leong CC, Syed NI, Lorscheider FL (2001) Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury. Neuroreport 12:733–737PubMedCrossRefGoogle Scholar
  52. Limson J, Nyokong T, Daya S (1998) The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study. J Pineal Res 24:15–21PubMedCrossRefGoogle Scholar
  53. Lorscheider FL, Vimy MJ, Summers AO (1995) Mercury exposure from “silver” tooth fillings: emerging evidence questions a traditional dental paradigm. FASEB J 9:504–508PubMedGoogle Scholar
  54. Lund JP, Mojon P, Pho M, Feine JS (2003) Alzheimer’s disease and edentulism. Age Ageing 32:228–229PubMedCrossRefGoogle Scholar
  55. Matsuoka M, Wispriyono B, Iryo Y, Igisu H (2000) Mercury chloride activates c-Jun N-terminal kinase and induces c-jun expression in LLC-PK1 cells. Toxicol Sci 53:361–368PubMedCrossRefGoogle Scholar
  56. McLachlan DR, Smith WL, Kruck TP (1993) Desferrioxamine and Alzheimer’s disease: video home behavior assessment of clinical course and measures of brain aluminum. Ther Drug Monit 15:602–607PubMedCrossRefGoogle Scholar
  57. Morris MC, Evans DA, Bienias JL et al (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 60:940–946PubMedCrossRefGoogle Scholar
  58. Mutter J, Naumann J, Sadaghiani C, Walach H, Drasch G (2004) Amalgam studies: disregarding basic principles of mercury toxicity. Int J Hyg Environ Health 205(8):435Google Scholar
  59. Nylander M (1986) Mercury in pituitary glands of dentists. Lancet 1:442PubMedCrossRefGoogle Scholar
  60. Nylander M, Weiner J (1991) Mercury and selenium concentrations and their interrelations in organs from dental staff and the general population. Br J Ind Med 48:729–734PubMedCentralPubMedGoogle Scholar
  61. Nylander M, Friberg L, Lind B (1987) Mercury concentrations in the human brain and kidneys in relation to exposure from dental amalgam fillings. Swed Dent J 11:179–187PubMedGoogle Scholar
  62. Olivieri G, Brack C, Muller-Spahn F, Stahelin HB, Herrmann M, Renard P, Brockhaus M, Hock C (2000) Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem 74:231–236PubMedCrossRefGoogle Scholar
  63. Olivieri G, Hess C, Savaskan E et al (2001) Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion. J Pineal Res 31:320–325PubMedCrossRefGoogle Scholar
  64. Olivieri G, Novakovic M, Savaskan E et al (2002) The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion. Neuroscience 113:849–855PubMedCrossRefGoogle Scholar
  65. Osuntokun BO, Hendrie HC, Ogunniyi AO et al (1992) Cross-cultural studies in Alzheimer’s disease. Ethn Dis 2:352–357PubMedGoogle Scholar
  66. Paganini-Hill A, Henderson VW (1994) Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 140:256–261PubMedGoogle Scholar
  67. Palkiewicz P, Zwiers H, Lorscheider FL (1994) ADP-ribosylation of brain neuronal proteins is altered by in vitro and in vivo exposure to inorganic mercury. J Neurochem 62:2049–2052PubMedCrossRefGoogle Scholar
  68. Pendergrass JC, Haley BE (1995) Mercury-EDTA complex specifically blocks brain beta-tubulin- GTP interactions: similarity to observations in Alzheimer’s disease. In: Friberg LT, Scrauzer GN (eds) Status quo and perspectives of amalgam and other dental materials. Georg Thieme Verlag, Stuttgart, pp 98–105Google Scholar
  69. Pendergrass JC, Haley BE (1996) Inhibition of brain tubulin-guanosine 5′-triphosphate interactions by mercury: similarity to observations in Alzheimer’s diseased brain. In: Sigel H, Sigel A (eds) Metal ions in biological systems, vol 34. Marcel Dekker, New York, pp 461–478Google Scholar
  70. Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL (1997) Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer’s diseased brain. Neurotoxicology 18:315–324PubMedGoogle Scholar
  71. Rajanna B, Chetty CS, Rajanna S, Hall E, Fail S, Yallapragada PR (1995) Modulation of protein kinase C by heavy metals. Toxicol Lett 81:197–203PubMedCrossRefGoogle Scholar
  72. Rapp SR, Espeland MA, Shumaker SA et al (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the women’s health initiative memory study: a randomized controlled trial. JAMA 289:2663–2672PubMedCrossRefGoogle Scholar
  73. Robinson SR (2001) Changes in the cellular distribution of glutamine synthetase in Alzheimer’s disease. J Neurosci Res 66:972–980PubMedCrossRefGoogle Scholar
  74. Sassin I, Schultz C, Thal DR et al (2000) Evolution of Alzheimer’s disease-related cytoskeletal changes in the basal nucleus of Meynert. Acta Neuropathol 100:259–269PubMedCrossRefGoogle Scholar
  75. Saxe SR, Wekstein MW, Kryscio RJ et al (1999) Alzheimer’s disease, dental amalgam and mercury. J Am Dent Assoc 130:191–199PubMedCrossRefGoogle Scholar
  76. Schober SE, Sinks TH, Jones RL et al (2003) Blood mercury levels in US children and women of childbearing age, 1999–2000. JAMA 289:1667–1674PubMedCrossRefGoogle Scholar
  77. Sierra EM, Tiffany-Castiglioni E (1991) Reduction of glutamine synthetase activity in astroglia exposed in culture to low levels of inorganic lead. Toxicology 65:295–304PubMedCrossRefGoogle Scholar
  78. Thompson CM, Markesbery WR, Ehmann WD, Mao YX, Vance DE (1988) Regional brain trace-element studies in Alzheimer’s disease. Neurotoxicology 9:1–7PubMedGoogle Scholar
  79. Tumani H, Shen G, Peter JB, Bruck W (1999) Glutamine synthetase in cerebrospinal fluid, serum, and brain: a diagnostic marker for Alzheimer disease? Arch Neurol 56:1241–1246PubMedCrossRefGoogle Scholar
  80. Vance DE, Ehmann WD, Markesbery WR (1988) Trace element imbalances in hair and nails of Alzheimer’s disease patients. Neurotoxicology 9:197–208PubMedGoogle Scholar
  81. Vance DE, Ehmann WD, Markesbery WR (1990) A search for longitudinal variations in trace element levels in nails of Alzheimer’s disease patients. Biol Trace Elem Res 26–27:461–470PubMedCrossRefGoogle Scholar
  82. Weiner JA, Nylander M (1993) The relationship between mercury concentration in human organs and different predictor variables. Sci Total Environ 138:101–115PubMedCrossRefGoogle Scholar
  83. Wenk GL (2003) Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64:7–10PubMedGoogle Scholar
  84. Wenstrup D, Ehmann WD, Markesbery WR (1990) Trace element imbalances in isolated subcellular fractions of Alzheimer’s disease. Brain Res 533:125–131PubMedCrossRefGoogle Scholar
  85. White AR, Huang X, Jobling MF et al (2001) Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem 76:1509–1520PubMedCrossRefGoogle Scholar

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© Springer India 2014

Authors and Affiliations

  • Shabnum Nabi
    • 1
  1. 1.Interdisciplinary Brain Research Centre (IBRC) Jawaharlal Nehru Medical CollegeAligarh Muslim UniversityAligarhIndia

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