Skip to main content

Advertisement

SpringerLink
Log in

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Although iron is essential in maintaining the function of the central nervous system, it is a potent source of reactive oxygen species. Excessive iron accumulation occurs in many neurodegenerative diseases including Alzheimer disease (AD), Parkinson’s disease, and Creutzfeldt-Jakob disease, raising the possibility that oxidative stress is intimately involved in the neurodegenerative process. AD in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Marlatt MW, Webber KM, Moreira PI et al (2005) Therapeutic opportunities in Alzheimer disease: one for all or all for one? Curr Med Chem 12:1137–1147

    Article  PubMed  CAS  Google Scholar 

  2. Castellani RJ, Lee HG, Zhu X et al (2006) Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl) 111:503–509

    Article  Google Scholar 

  3. Woods J, Snape M, Smith MA (2007) The cell cycle hypothesis of Alzheimer’s disease: suggestions for drug development. Biochim Biophys Acta 1772:503–508

    PubMed  CAS  Google Scholar 

  4. Rouault TA (2001) Systemic iron metabolism: a review and implications for brain iron metabolism. Pediatr Neurol 25:130–137

    Article  PubMed  CAS  Google Scholar 

  5. Rouault TA (2001) Iron on the brain. Nat Genet 28:299–300

    Article  PubMed  CAS  Google Scholar 

  6. Roy CN, Andrews NC (2001) Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers. Hum Mol Genet 10:2181–2186

    Article  PubMed  CAS  Google Scholar 

  7. Moos T (1996) Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. J Comp Neurol 375:675–692

    Article  PubMed  CAS  Google Scholar 

  8. Kawamata T, Tooyama I, Yamada T et al (1993) Lactotransferrin immunocytochemistry in Alzheimer and normal human brain. Am J Pathol 142:1574–1585

    PubMed  CAS  Google Scholar 

  9. Leveugle B, Spik G, Perl DP et al (1994) The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis. Brain Res 650:20–31

    Article  PubMed  CAS  Google Scholar 

  10. Patel BN, Dunn RJ, David S (2000) Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem 275:4305–4310

    Article  PubMed  CAS  Google Scholar 

  11. Klomp LW, Gitlin JD (1996) Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum Mol Genet 5:1989–1996

    Article  PubMed  CAS  Google Scholar 

  12. Crowe A, Morgan EH (1992) Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res 592:8–16

    Article  PubMed  CAS  Google Scholar 

  13. Bowman BH, Jansen L, Yang F et al (1995) Discovery of a brain promoter from the human transferrin gene and its utilization for development of transgenic mice that express human apolipoprotein E alleles. Proc Natl Acad Sci USA 92:12115–12119

    Article  PubMed  CAS  Google Scholar 

  14. Lieu PT, Heiskala M, Peterson PA et al (2001) The roles of iron in health and disease. Mol Aspects Med 22:1–87

    Article  PubMed  CAS  Google Scholar 

  15. Double KL, Zecca L, Costi P et al (2000) Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins. J Neurochem 75:2583–2589

    Article  PubMed  CAS  Google Scholar 

  16. Hentze MW, Kuhn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA 93:8175–8182

    Article  PubMed  CAS  Google Scholar 

  17. Connor JR, Menzies SL, Burdo JR et al (2001) Iron and iron management proteins in neurobiology. Pediatr Neurol 25:118–129

    Article  PubMed  CAS  Google Scholar 

  18. Calabrese V, Scapagnini G, Ravagna A et al (2002) Regional distribution of heme oxygenase, HSP70, and glutathione in brain: relevance for endogenous oxidant/antioxidant balance and stress tolerance. J Neurosci Res 68:65–75

    Article  PubMed  CAS  Google Scholar 

  19. Maines MD (2000) The heme oxygenase system and its functions in the brain. Cell Mol Biol (Noisy-le-grand) 46:573–585

    CAS  Google Scholar 

  20. Marcus DL, Thomas C, Rodriguez C et al (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 150:40–44

    Article  PubMed  CAS  Google Scholar 

  21. Sayre LM, Zelasko DA, Harris PL et al (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 68:2092–2097

    Article  PubMed  CAS  Google Scholar 

  22. Smith MA, Richey Harris PL, Sayre LM et al (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657

    PubMed  CAS  Google Scholar 

  23. Smith MA, Taneda S, Richey PL et al (1994) Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA 91:5710–5714

    Article  PubMed  CAS  Google Scholar 

  24. Smith MA, Perry G, Richey PL et al (1996) Oxidative damage in Alzheimer’s. Nature 382:120–121

    Article  PubMed  CAS  Google Scholar 

  25. Smith MA, Harris PL, Sayre LM et al (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 94:9866–9868

    Article  PubMed  CAS  Google Scholar 

  26. Nunomura A, Perry G, Pappolla MA et al (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 19:1959–1964

    PubMed  CAS  Google Scholar 

  27. Zhou Y, Richardson JS, Mombourquette MJ et al (1995) Free radical formation in autopsy samples of Alzheimer and control cortex. Neurosci Lett 195:89–92

    Article  PubMed  CAS  Google Scholar 

  28. Martins RN, Harper CG, Stokes GB et al (1986) Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer’s disease may reflect oxidative stress. J Neurochem 46:1042–1045

    Article  PubMed  CAS  Google Scholar 

  29. Pappolla MA, Omar RA, Kim KS et al (1992) Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease. Am J Pathol 140:621–628

    PubMed  CAS  Google Scholar 

  30. Lovell MA, Robertson JD, Teesdale WJ et al (1998) Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 158:47–52

    Article  PubMed  CAS  Google Scholar 

  31. Hall ED, Oostveen JA, Dunn E et al (1995) Increased amyloid protein precursor and apolipoprotein E immunoreactivity in the selectively vulnerable hippocampus following transient forebrain ischemia in gerbils. Exp Neurol 135:17–27

    Article  PubMed  CAS  Google Scholar 

  32. Shi J, Perry G, Smith MA et al (2000) Vascular abnormalities: the insidious pathogenesis of Alzheimer’s disease. Neurobiol Aging 21:357–361

    Article  PubMed  CAS  Google Scholar 

  33. Abe K, St George-Hyslop PH, Tanzi RE et al (1991) Induction of amyloid precursor protein mRNA after heat shock in cultured human lymphoblastoid cells. Neurosci Lett 125:169–171

    Article  PubMed  CAS  Google Scholar 

  34. Jendroska K, Poewe W, Daniel SE et al (1995) Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol (Berl) 90:461–466

    CAS  Google Scholar 

  35. Murakami N, Yamaki T, Iwamoto Y et al (1998) Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus. J Neurotrauma 15:993–1003

    Article  PubMed  CAS  Google Scholar 

  36. Shi J, Xiang Y, Simpkins JW (1997) Hypoglycemia enhances the expression of mRNA encoding beta-amyloid precursor protein in rat primary cortical astroglial cells. Brain Res 772:247–251

    Article  PubMed  CAS  Google Scholar 

  37. Mattson MP, Pedersen WA (1998) Effects of amyloid precursor protein derivatives and oxidative stress on basal forebrain cholinergic systems in Alzheimer’s disease. Int J Dev Neurosci 16:737–753

    Article  PubMed  CAS  Google Scholar 

  38. Gabuzda D, Busciglio J, Chen LB et al (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269:13623–13628

    PubMed  CAS  Google Scholar 

  39. Misonou H, Morishima-Kawashima M, Ihara Y (2000) Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry (Mosc) 39:6951–6959

    Article  CAS  Google Scholar 

  40. 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 31:320–325

    Article  PubMed  CAS  Google Scholar 

  41. Frederikse PH, Garland D, Zigler JS Jr et al (1996) Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J Biol Chem 271:10169–10174

    Article  PubMed  CAS  Google Scholar 

  42. Paola D, Domenicotti C, Nitti M et al (2000) Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 268:642–646

    Article  PubMed  CAS  Google Scholar 

  43. Atwood CS, Scarpa RC, Huang X et al (2000) Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1–42. J Neurochem 75:1219–1233

    Article  PubMed  CAS  Google Scholar 

  44. Atwood CS, Moir RD, Huang X et al (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273:12817–12826

    Article  PubMed  CAS  Google Scholar 

  45. Curtain CC, Ali F, Volitakis I et al (2001) Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 276:20466–20473

    Article  PubMed  CAS  Google Scholar 

  46. Huang X, Atwood CS, Hartshorn MA et al (1999) The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry (Mosc) 38:7609–7616

    Article  CAS  Google Scholar 

  47. Dikalov SI, Vitek MP, Maples KR et al (1999) Amyloid beta peptides do not form peptide-derived free radicals spontaneously, but can enhance metal-catalyzed oxidation of hydroxylamines to nitroxides. J Biol Chem 274:9392–9399

    Article  PubMed  CAS  Google Scholar 

  48. Perry G, Nunomura A, Raina AK et al (2000) Amyloid-beta junkies. Lancet 355:757

    Article  PubMed  CAS  Google Scholar 

  49. Smith MA, Joseph JA, Perry G (2000) Arson. Tracking the culprit in Alzheimer’s disease. Ann NY Acad Sci 924:35–38

    Article  PubMed  CAS  Google Scholar 

  50. Joseph J, Shukitt-Hale B, Denisova NA et al (2001) Copernicus revisited: amyloid beta in Alzheimer’s disease. Neurobiol Aging 22:131–146

    Article  PubMed  CAS  Google Scholar 

  51. Rottkamp CA, Raina AK, Zhu X et al (2001) Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med 30:447–450

    Article  PubMed  CAS  Google Scholar 

  52. Rottkamp CA, Atwood CS, Joseph JA et al (2002) The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides 23:1333–1341

    Article  PubMed  CAS  Google Scholar 

  53. Cullen KM (1997) Perivascular astrocytes within Alzheimer’s disease plaques. Neuroreport 8:1961–1966

    Article  PubMed  CAS  Google Scholar 

  54. Dunn CJ (1991) Cytokines as mediators of chronic inflammatory disease. In: Kimball ES (ed) Cytokines and inflammation. CRC, Boca Raton, FL, pp 1–33

    Google Scholar 

  55. Yoshida T, Tanaka M, Sotomatsu A et al (1998) Activated microglia cause iron-dependent lipid peroxidation in the presence of ferritin. Neuroreport 9:1929–1933

    Article  PubMed  CAS  Google Scholar 

  56. Cadman ED, Witte DG, Lee CM (1994) Regulation of the release of interleukin-6 from human astrocytoma cells. J Neurochem 63:980–987

    Article  PubMed  CAS  Google Scholar 

  57. Sayre LM, Perry G, Harris PL et al (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem 74:270–279

    Article  PubMed  CAS  Google Scholar 

  58. Shan X, Tashiro H, Lin CL (2003) The identification and characterization of oxidized RNAs in Alzheimer’s disease. J Neurosci 23:4913–4921

    PubMed  CAS  Google Scholar 

  59. Honda K, Smith MA, Zhu X et al (2005) Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem 280:20978–20986

    Article  PubMed  CAS  Google Scholar 

  60. Hirai K, Aliev G, Nunomura A et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    PubMed  CAS  Google Scholar 

  61. Mikhaylova A, Davidson M, Toastmann H et al (2005) Detection, identification and mapping of iron anomalies in brain tissue using X-ray absorption spectroscopy. J R Soc Interface/R Soc 2:33–37

    Article  CAS  Google Scholar 

  62. Collingwood JF, Mikhaylova A, Davidson M et al (2005) In situ characterization and mapping of iron compounds in Alzheimer’s disease tissue. J Alzheimers Dis 7:267–272

    PubMed  CAS  Google Scholar 

  63. Collingwood JF, Mikhaylova A, Davidson MR et al (2005) High-resolution x-ray absorption spectroscopy studies of metal compounds in neurodegenerative brain tissue. J Phys: Conf Ser 17:54–60

    Article  CAS  Google Scholar 

  64. Dobson J, Grassi P (1996) Magnetic properties of human hippocampal tissue—evaluation of artefact and contamination sources. Brain Res Bull 39:255–259

    Article  PubMed  CAS  Google Scholar 

  65. Schultheiss-Grassi PP, Wessiken R, Dobson J (1999) TEM investigations of biogenic magnetite extracted from the human hippocampus. Biochim Biophys Acta 1426:212–216

    PubMed  CAS  Google Scholar 

  66. Kirschvink JL, Kobayashi-Kirschvink A, Woodford BJ (1992) Magnetite biomineralization in the human brain. Proc Natl Acad Sci USA 89:7683–7687

    Article  PubMed  CAS  Google Scholar 

  67. Hautot D, Pankhurst QA, Khan N et al (2003) Preliminary evaluation of nanoscale biogenic magnetite in Alzheimer’s disease brain tissue. Proceedings 270(Suppl 1):S62–S64

    PubMed  CAS  Google Scholar 

  68. Dobson J (2001) Nanoscale biogenic iron oxides and neurodegenerative disease. FEBS Lett 496:1–5

    Article  PubMed  CAS  Google Scholar 

  69. Dobson J (2004) Magnetic iron compounds in neurological disorders. Ann NY Acad Sci 1012:183–192

    Article  PubMed  CAS  Google Scholar 

  70. Timmel CR, Till U, Brocklehurst B et al (1998) Effects of weak magnetic fields on free radical recombination reactions. Mol Phys 95:71–89

    Article  CAS  Google Scholar 

  71. Scaiano JC, Monahan S, Renaud J (1997) Dramatic effect of magnetite particles on the dynamics of photogenerated free radicals. Photochem Photobiol 65:759–762

    CAS  Google Scholar 

  72. Bush AI (2002) Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol Aging 23:1031–1038

    Article  PubMed  CAS  Google Scholar 

  73. Shachar DB, Kahana N, Kampel V et al (2004) Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology 46:254–263

    Article  PubMed  CAS  Google Scholar 

  74. Bartzokis G, Tishler TA, Lu PH et al (2007) Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging 28:414–423

    Article  PubMed  CAS  Google Scholar 

  75. Jack CR Jr, Wengenack TM, Reyes DA et al (2005) In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer’s transgenic mice. J Neurosci 25:10041–10048

    Article  PubMed  CAS  Google Scholar 

  76. Ritchie CW, Bush AI, Mackinnon A 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 

  77. McLachlan DR, Kruck TP, Lukiw WJ et al (1991) Would decreased aluminum ingestion reduce the incidence of Alzheimer’s disease? CMAJ 145:793–804

    PubMed  CAS  Google Scholar 

  78. Liu G, Garrett MR, Men P et al (2005) Nanoparticle and other metal chelation therapeutics in Alzheimer disease. Biochim Biophys Acta 1741:246–252

    PubMed  CAS  Google Scholar 

  79. Smith MA, Atwood CS, Joseph JA et al (2002) Predicting the failure of amyloid-beta vaccine. Lancet 359:1864–1865

    Article  PubMed  Google Scholar 

  80. Lee HG, Casadesus G, Zhu X et al (2004) Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann NY Acad Sci 1019:1–4

    Article  PubMed  CAS  Google Scholar 

  81. 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 37:899–909

    Article  PubMed  CAS  Google Scholar 

  82. Cherny RA, Atwood CS, Xilinas ME 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  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Institutes of Health, the Alzheimer’s Association, and Philip Morris USA Inc., and Philip Morris International.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Maryland, Baltimore, MD, USA

    Rudy J. Castellani

  2. Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, Coimbra, Portugal

    Paula I. Moreira

  3. Department of Radiology, University of Utah, Salt Lake City, UT, USA

    Gang Liu

  4. Institute of Science and Technology in Medicine, Keele University, Staffordshire, UK

    Jon Dobson

  5. College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA

    George Perry

  6. Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA

    George Perry, Mark A. Smith & Xiongwei Zhu

Authors
  1. Rudy J. Castellani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paula I. Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jon Dobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark A. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiongwei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark A. Smith.

Additional information

Special issue dedicated to Dr. Moussa Youdim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castellani, R.J., Moreira, P.I., Liu, G. et al. Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease. Neurochem Res 32, 1640–1645 (2007). https://doi.org/10.1007/s11064-007-9360-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9360-7

Keywords

Search

Navigation