Molecular and Cellular Biochemistry

, Volume 345, Issue 1–2, pp 91–104 | Cite as

Metals, oxidative stress and neurodegenerative disorders

  • Klaudia JomovaEmail author
  • Dagmar Vondrakova
  • Michael Lawson
  • Marian ValkoEmail author


The neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), are age-related disorders characterized by the deposition of abnormal forms of specific proteins in the brain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main constituent is fibrillar aggregates of a 39–42 residue peptide referred to as the amyloid-β protein (Aβ). PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein. There are various factors influencing the pathological depositions, and in general, the cause of neuronal death in neurological disorders appears to be multifactorial. However, it is clear, that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation. The increased level of oxidative stress in AD brain is reflected by the increased brain content of iron (Fe) and copper (Cu) both capable of stimulating free radical formation (e.g. hydroxyl radicals via Fenton reaction), increased protein and DNA oxidation in the AD brain, enhanced lipid peroxidation, decreased level of cytochrome c oxidase and advanced glycation end products (AGEs), carbonyls, malondialdehyde (MDA), peroxynitrite, and heme oxygenase-1 (HO-1). AGEs, mainly through their interaction with receptors for advanced glycation end products (RAGEs), further activate signaling pathways, inducing formation of proinflammatory cytokines such as interleukin-6 (IL-6). The conjugated aromatic ring of tyrosine residues is a target for free-radical attack, and accumulation of dityrosine and 3-nitrotyrosine has also been reported in AD brain. The oxidative stress linked with PD is supported by both postmortem studies and by studies showing the increased level of oxidative stress in the substantia nigra pars compacta, demonstrating thus the capacity of oxidative stress to induce nigral cell degeneration. Markers of lipid peroxidation include 4-hydroxy-trans-2-nonenal (HNE), 4-oxo-trans-2-nonenal (4-ONE), acrolein, and 4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. In addition, other important factors, involving inflammation, toxic action of nitric oxide (NO·), defects in protein clearance, and mitochondrial dysfunction all contribute to the etiology of PD. It has been suggested that several individual antioxidants or their combinations can be neuroprotective and decrease the risk of AD or slow its progression. The aim of this review is to discuss the role of redox metals Fe and Cu and non-redox metal zinc (Zn) in oxidative stress-related etiology of AD and PD. Attention is focused on the metal-induced formation of free radicals and the protective role of antioxidants [glutathione (GSH), vitamin C (ascorbic acid)], vitamin E (α-Tocopherol), lipoic acid, flavonoids [catechins, epigallocatechin gallate (EGCG)], and curcumin. An alternate hypothesis topic in AD is also discussed.


Iron Copper Zinc Alzheimer’s disease Parkinson’s disease Oxidative stress Free radicals Antioxidants 



We thank the Slovak Grant Agency (Projects VEGA/1/0575/08 and 1/0213/08) for financial support. This study was also supported by the Slovak Research and Development Agency under the contract No. VVCE-0004-07.


  1. 1.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMedGoogle Scholar
  2. 2.
    Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214PubMedCrossRefGoogle Scholar
  3. 3.
    Bush AI (2003) The metallobiology of Alzheimer′s disease. Trends Neurosci 26:207–214PubMedCrossRefGoogle Scholar
  4. 4.
    Sayre LM, Smith MA, Perry G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8:721–738PubMedGoogle Scholar
  5. 5.
    Varadarajan S, Yatin S, Aksenova M, Butterfield DA (2000) Review: Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130:184–208PubMedCrossRefGoogle Scholar
  6. 6.
    Lee HG, Zhu XW, Castellani RJ, Nunomura A, Perry G, Smith MA (2007) Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther 321:823–829PubMedCrossRefGoogle Scholar
  7. 7.
    Pimplikar SW (2009) Reassessing the amyloid cascade hypothesis of Alzheimer′s disease. Int J Biochem Cell Biol 41:1261–1268PubMedCrossRefGoogle Scholar
  8. 8.
    Devi L, Anandatheerthavarada HK (2010) Mitochondrial trafficking of APP and alpha synuclein: relevance to mitochondrial dysfunction in Alzheimer′s and Parkinson′s diseases. Biochim Biophys Acta 1802:11–19PubMedGoogle Scholar
  9. 9.
    Tillement JP, Lecanu L, Papadopoulos V (2010) Amyloidosis and neurodegenerative diseases: current treatments and new pharmacological options. Pharmacology 85:1–17PubMedCrossRefGoogle Scholar
  10. 10.
    Block ML, Calderon-Garciduenas L (2009) Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci 32:506–516PubMedCrossRefGoogle Scholar
  11. 11.
    Bush AI, Curtain CC (2008) Twenty years of metallo-neurobiology: where to now? Eur Biophys J Biophys Lett 37:241–245Google Scholar
  12. 12.
    Jenner P, Olanow CW (1998) Understanding cell death in Parkinson′s disease. Ann Neurol 44:S72–S84PubMedGoogle Scholar
  13. 13.
    Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822PubMedCrossRefGoogle Scholar
  14. 14.
    Cadenas E, Davies KJA (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29:222–230PubMedCrossRefGoogle Scholar
  15. 15.
    Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine, 4th edn. Oxford University Press, OxfordGoogle Scholar
  16. 16.
    Liochev SI, Fridovich I (1994) The role of O2 in the production of HO: in vitro and in vivo. Free Radic Biol Med 16:29–33PubMedCrossRefGoogle Scholar
  17. 17.
    Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:37–56PubMedCrossRefGoogle Scholar
  18. 18.
    Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84PubMedCrossRefGoogle Scholar
  19. 19.
    Ghafourifar P, Cadenas E (2005) Mitochondrial nitric oxide synthase. Trends Pharmacol Sci 26:190–195PubMedCrossRefGoogle Scholar
  20. 20.
    Denninger JW, Marletta MA (1999) Guanylate cyclase and the (NO)-N-/cGMP signaling pathway. Biochim Biophys Acta 1411:334–350PubMedCrossRefGoogle Scholar
  21. 21.
    Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  22. 22.
    Hardy J, Selkoe DJ (2002) Medicine—the amyloid hypothesis of Alzheimer′s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  23. 23.
    Valko M, Morris H, Cronin MTD (2005) Metals, toxicity and oxidative stress. Curr Med Chem 11:1161–1208CrossRefGoogle Scholar
  24. 24.
    Rajendran R, Ren MQ, Ynsa MD et al (2009) A novel approach to the identification and quantitative elemental analysis of amyloid deposits-insights into the pathology of Alzheimer’s disease. Biochem Biophys Res Commun 382:91–95PubMedCrossRefGoogle Scholar
  25. 25.
    Atwood CS, Moir RD, Huang XD et al (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273:12817–12826PubMedCrossRefGoogle Scholar
  26. 26.
    Chafekar SM, Hoozemans JJM, Zwart R et al (2007) Abeta (1–42) induces mild endoplasmic reticulum stress in an aggregation state-dependent manner. Antioxid Redox Signal 9:2245–2254PubMedCrossRefGoogle Scholar
  27. 27.
    Hung YH, Bush AI, Cherny RA (2010) Copper in the brain and Alzheimer’s disease. J Biol Inorg Chem 15:61–76PubMedCrossRefGoogle Scholar
  28. 28.
    Cuanjungco MP, Goldstein LE, Nunomura A et al (2000) Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of A beta by zinc. J Biol Chem 275:19439–19442Google Scholar
  29. 29.
    Halliwell B (2001) Role of free radicals in the neurodegenerative diseases—therapeutic implications for antioxidant treatment. Drugs Aging 18:685–716PubMedCrossRefGoogle Scholar
  30. 30.
    Premkumar DR, Smith MA, Richey PL, Petersen RB, Castellani R, Kutty RK, Wiggert B, Perry G, Kalaria RN (1995) Induction of heme oxygenase-1 messenger-RNA and protein in neocortex and cerebral vessels in Alzheimer’s-disease. J Neurochem 65:1399–1402PubMedCrossRefGoogle Scholar
  31. 31.
    Nunomura A, Perry G, Zhang J, Montine TJ, Takeda A, Chiba S, Smith MA (1999) RNA oxidation in Alzheimer and Parkinson diseases. J Anti-Aging Med 2:227–230Google Scholar
  32. 32.
    Huang XD, Cuajungco MP, Atwood CS et al (1999) Cu(II) potentiation of Alzheimer abeta neurotoxicity—correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274:37111–37116PubMedCrossRefGoogle Scholar
  33. 33.
    Cerpa WF, Barria MI, Chacon MA, Suazo M, Gonzalez M, Opazo C, Bush AI, Inestrosa NC (2004) The N-terminal copper-binding domain of the amyloid precursor protein protects against Cu2+ neurotoxicity in vivo. FASEB J 18:1701PubMedGoogle Scholar
  34. 34.
    Pogocki D (2003) Alzheimer’s beta-amyloid peptide as a source of neurotoxic free radicals: the role of structural effects. Acta Neurobiol Exp 63:131–145Google Scholar
  35. 35.
    Schoneich C, Pogocki D, Hug GL, Bobrowski K (2003) Free radical reactions of methionine in peptides: mechanisms relevant to beta-amyloid oxidation and Alzheimer’s disease. J Am Chem Soc 125:13700–13713PubMedCrossRefGoogle Scholar
  36. 36.
    da Silva GF, Lykourinou V, Angerhofer A, Ming LJ (2009) Methionine does not reduce Cu(II)-beta-amyloid!—rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)-beta-amyloid. Biochim Biophys Acta 1792:49–55PubMedGoogle Scholar
  37. 37.
    Hider RC, Ma Y, Molina-Holgado F et al (2008) Iron chelation as a potential therapy for neurodegenerative disease. Biochem Soc Trans 36:1304–1308PubMedCrossRefGoogle Scholar
  38. 38.
    Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240PubMedGoogle Scholar
  39. 39.
    Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer’s disease amyloid beta peptide. Biochim Biophys Acta 1768:1976–1990PubMedCrossRefGoogle Scholar
  40. 40.
    White AR, Du T, Laughton KM, Volitakis I et al (2006) Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J Biol Chem 281:17670–17680PubMedCrossRefGoogle Scholar
  41. 41.
    Crouch PJ, Tew DJ, Du T et al (2009) Restored degradation of the Alzheimer’s amyloid-beta peptide by targeting amyloid formation. J Neurochem 108:1198–1207PubMedCrossRefGoogle Scholar
  42. 42.
    Ritchie CW, Bush AI, Mackinnon A (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease—a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691PubMedCrossRefGoogle Scholar
  43. 43.
    Garai K, Sahoo B, Kaushalya SK et al (2007) Zinc lowers amyloid-beta toxicity by selectively precipitating aggregation intermediates. Biochemistry 46:10655–10663PubMedCrossRefGoogle Scholar
  44. 44.
    Cuajungco MP, Lees GJ (1998) Nitric oxide generators produce accumulation of chelatable zinc in hippocampal neuronal perikarya. Brain Res 799:118–129PubMedCrossRefGoogle Scholar
  45. 45.
    Cuajungco MP, Faget KY (2003) Zinc takes the center stage: its paradoxical role in Alzheimer’s disease. Brain Res Rev 41:44–56PubMedCrossRefGoogle Scholar
  46. 46.
    Ong WY, Halliwell B (2004) Iron, atherosclerosis, and neurodegeneration–a key role for cholesterol in promoting iron-dependent oxidative damage? Ann N Y Acad Sci 1012:51–64PubMedCrossRefGoogle Scholar
  47. 47.
    Ghribi O, Golovko MY, Larsen B et al (2006) Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets. J Neurochem 99:438–449PubMedCrossRefGoogle Scholar
  48. 48.
    Kojo S (2004) Vitamin C: basic metabolism and its function as an index of oxidative stress. Curr Med Chem 11:1041–1064PubMedCrossRefGoogle Scholar
  49. 49.
    Carr A, Frei B (1999) Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 13:1007–1024PubMedGoogle Scholar
  50. 50.
    Kasparova S, Brezova V, Valko M et al (2005) Study of the oxidative stress in a rat model of chronic brain hypoperfusion. Neurochem Int 46:601–611PubMedCrossRefGoogle Scholar
  51. 51.
    Cuzzorcrea S, Thiemermann C, Salvemini D (2004) Potential therapeutic effect of antioxidant therapy in shock and inflammation. Curr Med Chem 11:1147–1162Google Scholar
  52. 52.
    Dikalov SI, Vitek MP, Mason RP (2004) Cupric-amyloid beta peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical. Free Radic Biol Med 36:340–347PubMedCrossRefGoogle Scholar
  53. 53.
    Shearer J, Szalai VA (2008) The amyloid-beta peptide of Alzheimer’s disease binds Cu-I in a linear bis-his coordination environment: insight into a possible neuroprotective mechanism for the amyloid-beta peptide. J Am Chem Soc 130:17826–17835PubMedCrossRefGoogle Scholar
  54. 54.
    Ryglewicz D, Rodo M, Kunicki PK, Bednarska-Makaruk M et al (2002) Plasma antioxidant activity and vascular dementia. J Neurol Sci 203–204:195–197PubMedCrossRefGoogle Scholar
  55. 55.
    Butterfield DA, Castegna A, Pocernich ChB et al (2002) Nutritional approaches to combat oxidative stress in Alzheimer’s disease. J Nutr Biochem 13:444–461PubMedCrossRefGoogle Scholar
  56. 56.
    McGrath LT, McGleenon BM, Brennan S et al (2001) Increased oxidative stress in Alzheimer’s disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM 94:485–490PubMedCrossRefGoogle Scholar
  57. 57.
    Riviere S, Birlouez-Aragon I, Nourhashemi F (1998) Low plasma vitamin C in Alzheimer patients despite an adequate diet. Int J Geriatr Psychiatry 13:749–754PubMedCrossRefGoogle Scholar
  58. 58.
    Foy CJ, Passmore AP, Vahidassr MD et al (1999) Plasma chain-breaking antioxidants in Alzheimer’s disease, vascular dementia and Parkinson’s disease. QJM 92:39–45PubMedCrossRefGoogle Scholar
  59. 59.
    Schippling S, Kontush A, Arlt S et al (2000) Increased lipoprotein oxidation in Alzheimer’s disease. Free Radic Biol Med 28:351–360PubMedCrossRefGoogle Scholar
  60. 60.
    Kontush A, Mann U, Arlt S et al (2001) Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer’s disease. Free Radic Biol Med 31:345–354PubMedCrossRefGoogle Scholar
  61. 61.
    Petersen RC, Thomas RG, Grundman M et al (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388PubMedCrossRefGoogle Scholar
  62. 62.
    Kontush A, Schekatolina S (2006) Vitamin E in neurodegenerative disorders: Alzheimer’s disease. Ann N Y Acad Sci 1031:249–262CrossRefGoogle Scholar
  63. 63.
    Azzi A, Gysin R, Kempna P, Ricciarelli R, Villacorta L, Visarius T, Zingg J-M (2003) The role of α-tocopherol in preventing disease: from epidemiology to molecular events. Mol Asp Med 24:325–336CrossRefGoogle Scholar
  64. 64.
    Masella R, Di Benedetto R, Vari C et al (2005) Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 16:577–586PubMedCrossRefGoogle Scholar
  65. 65.
    Ji YB, Akerboom TPM, Sies H, Thomas JA (1999) S-nitrosylation and S-glutathiolation of protein sulfhydryls by S-nitroso glutathione. Arch Biochem Biophys 362:67–78PubMedCrossRefGoogle Scholar
  66. 66.
    Karoui H, Hogg N, Frejaville C et al (1996) Characterization of sulfur-centered radical intermediates formed during the oxidation of thiols and sulfite by peroxynitrite ESR-spin trapping and oxygen uptake studies. J Biol Chem 271:6000–6009PubMedCrossRefGoogle Scholar
  67. 67.
    Ansari MA, Scheff SW (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69:155–167PubMedCrossRefGoogle Scholar
  68. 68.
    Packer L, Witt EH, Tritschler HJ (1995) Alfa-lipoic acid as a biological antioxidant. Free Radic Biol Med 19:227–250PubMedCrossRefGoogle Scholar
  69. 69.
    Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM (2004) Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem 11:1135–1146PubMedGoogle Scholar
  70. 70.
    Packer L, Tritschler HJ, Wessel K (1997) Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 22:359–378PubMedCrossRefGoogle Scholar
  71. 71.
    Holmquist L, Stuchbury G, Berbaum K et al (2007) Lipoic acid as a novel treatment for Alzheimer′s disease and related dementias. Pharmacol Ther 113:154–164PubMedCrossRefGoogle Scholar
  72. 72.
    Maczurek A, Hagera K, Kenkliesa K et al (2008) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer′s disease. Adv Drug Deliv Rev 60:1463–1470PubMedCrossRefGoogle Scholar
  73. 73.
    Suh JH, Zhu BZ, De Szoeke E, Frei B, Hagen TM (2004) Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep 9:57–61PubMedCrossRefGoogle Scholar
  74. 74.
    Cavalli A, Bolognesi ML, Minarini A et al (2008) Multi-target-directed ligands to combat at neurodegenerative diseases. J Med Chem 51:347–372PubMedCrossRefGoogle Scholar
  75. 75.
    Rice Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956PubMedCrossRefGoogle Scholar
  76. 76.
    Thielecke F, Boschmann M (2009) The potential role of green tea catechins in the prevention of the metabolic syndrome–a review. Phytochemistry 70:11–24PubMedCrossRefGoogle Scholar
  77. 77.
    Choi YT, Jung CH, Lee SR et al (2001) The green tea polyphenol (−)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 7:603–614CrossRefGoogle Scholar
  78. 78.
    Guo QN, Zhao BL, Li MF, Shen SR, Xin WJ (1996) Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1304:210–222PubMedGoogle Scholar
  79. 79.
    Mandel S, Amit T, Reznichenko L (2006) Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. Mol Nutr Food Res 50:229–234PubMedCrossRefGoogle Scholar
  80. 80.
    Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K (2010) EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci USA 107:7710–7715PubMedCrossRefGoogle Scholar
  81. 81.
    Kumamoto M, Sonda T, Nagayama K et al (2001) Effects of pH and metal ions on antioxidative activities of catechins. Biosci Biotechnol Biochem 65:126–132PubMedCrossRefGoogle Scholar
  82. 82.
    Grinberg LN, Newmark H, Kitrossky N et al (1997) Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 54:973–978PubMedCrossRefGoogle Scholar
  83. 83.
    Rogers JT, Randall JD, Cahill CM et al (2002) An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 277:45518–45528PubMedCrossRefGoogle Scholar
  84. 84.
    Mandel SA, Amit T, Zheng H et al (2006) The essentiality of iron chelation in neuroprotection: a potential role of green tea catechins. In: Luo Y, Packer L (eds) Oxidative stress and age-related neurodegeneration. Taylor & Francis Group, Boca Raton, pp 277–299Google Scholar
  85. 85.
    Dedeoglu A, Cormier K, Payton S et al (2004) Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer’s amyloidogenesis. Exp Gerontol 39:1641–1649PubMedCrossRefGoogle Scholar
  86. 86.
    Hsiao K, Chapman P, Nilsen S et al (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedCrossRefGoogle Scholar
  87. 87.
    Hanson ES, Rawlins ML, Leibold EA (2003) Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 278:40337–40342PubMedCrossRefGoogle Scholar
  88. 88.
    Wang J, Chen G, Muckenthaler M et al (2004) Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol 24:954–965PubMedCrossRefGoogle Scholar
  89. 89.
    Preetha A, Thomas SG, Kunnumakkaraa AB et al (2008) Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol 76:1590–1611CrossRefGoogle Scholar
  90. 90.
    Singhal SS, Awasthi S, Pandya U et al (1999) The effect of curcumin on glutathione-linked enzymes in K562 human leukemia cells. Toxicol Lett 109:87–95PubMedCrossRefGoogle Scholar
  91. 91.
    Kim DS, Park SY, Kim JK (2001) Curcuminoids from Curcuma longa L. (Zinggiveraceae) that protect PC12 rate pheochromocytoma and normal human umbilical vein endothelial cells from betaA (1–42) insult. Neurosci Lett 303:57–61PubMedCrossRefGoogle Scholar
  92. 92.
    Ganguli M, Chandra V, Kamboh MI (2000) Apolipoprotein E polymorphism and Alzheimer disease: the Indo-US Cross-National Dementia Study. Arch Neurol 57:824–830PubMedCrossRefGoogle Scholar
  93. 93.
    Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370–8377PubMedGoogle Scholar
  94. 94.
    Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890PubMedCrossRefGoogle Scholar
  95. 95.
    Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185PubMedCrossRefGoogle Scholar
  96. 96.
    Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRefGoogle Scholar
  97. 97.
    Selkoe DJ, Wolfe MS (2007) Presenilin: running with scissors in the membrane. Cell 131:215–221PubMedCrossRefGoogle Scholar
  98. 98.
    Gong CX, Iqbal K (2008) Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 15:2321–2328PubMedCrossRefGoogle Scholar
  99. 99.
    Jenner P (2003) Oxidative stress in Parkinson′s disease. Ann Neurol 53:S26–S36PubMedCrossRefGoogle Scholar
  100. 100.
    Ebadi M, Srinivasan SK, Baxi MD (1996) Oxidative stress and antioxidant therapy in Parkinson’s disease. Prog Neurobiol 48:1–19PubMedCrossRefGoogle Scholar
  101. 101.
    Eriksen J, Dawson T, Dickson D, Petrucelli L (2003) Caught in the act: α-synuclein is the culprit in Parkinson’s disease. Neuron 40:453–456PubMedCrossRefGoogle Scholar
  102. 102.
    Gasser T (2001) Genetics of Parkinson’s disease. J Neurol 248:833–840PubMedCrossRefGoogle Scholar
  103. 103.
    Cooper AA, Gitler AD, Cashikar A et al (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328PubMedCrossRefGoogle Scholar
  104. 104.
    Winklhofer KF, Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta 1802:29–44PubMedGoogle Scholar
  105. 105.
    Chinta SJ, Andersen JK (2008) Redox imbalance in Parkinson′s disease. Biochim Biophys Acta 1780:1362–1367PubMedGoogle Scholar
  106. 106.
    Kraytsberg Y, Kudryavtseva E, McKee AC et al (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38:518–520PubMedCrossRefGoogle Scholar
  107. 107.
    Bender A, Krishnan KJ, Morris CM et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517PubMedCrossRefGoogle Scholar
  108. 108.
    Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10:S18–S25PubMedCrossRefGoogle Scholar
  109. 109.
    Jenner P, Olanow CW (2006) The pathogenesis of cell death in Parkinson’s disease. Neurology 66:S24–S36PubMedGoogle Scholar
  110. 110.
    Kaur D, Yantiri F, Rajagopalan S et al (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37:899–909PubMedCrossRefGoogle Scholar
  111. 111.
    Bogaerts V, Theuns J, van Broeckhoven C (2008) Genetic findings in Parkinson’s disease and translation into treatment: a leading role for mitochondria? Genes Brain Behav 7:129–151PubMedCrossRefGoogle Scholar
  112. 112.
    Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract 4:600–609CrossRefGoogle Scholar
  113. 113.
    Paisan-Ruiz C, Jain S, Evans EW et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600PubMedCrossRefGoogle Scholar
  114. 114.
    Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607PubMedCrossRefGoogle Scholar
  115. 115.
    Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160PubMedCrossRefGoogle Scholar
  116. 116.
    Gandhi S, Wood-Kaczmar A, Yao Z (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33:627–638PubMedCrossRefGoogle Scholar
  117. 117.
    Moore DJ (2006) Parkin: a multifaceted ubiquitin ligase. Biochem Soc Trans 34:749–753PubMedCrossRefGoogle Scholar
  118. 118.
    Meulener M, Whitworth AJ, Armstrong-Gold CE et al (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson’s disease. Curr Biol 15:1572–1577PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of Natural SciencesConstantine The Philosopher UniversityNitraSlovakia
  2. 2.Department of CardiologyNa Homolce HospitalPragueCzech Republic
  3. 3.Faculty of Chemical and Food TechnologySlovak Technical UniversityBratislavaSlovakia

Personalised recommendations