Neurobiology of Aging
Volume 28, Issue 3 , Pages 414-423 , March 2007

Brain ferritin iron may influence age- and gender-related risks of neurodegeneration

  • George Bartzokis

      Affiliations

    • Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
    • Laboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, UCLA, Los Angeles, CA 90095, United States
    • Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, United States
    • Corresponding Author InformationCorresponding author at: UCLA Alzheimer's Disease Research Center, 710 Westwood Plaza, Room 2-238, Los Angeles, CA 90095-1769, United States. Tel.: +1 310 206 3207; fax: +1 310 268 3266.
  • ,
  • Todd A. Tishler

      Affiliations

    • Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
    • Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, United States
    • Neuroscience Interdepartmental Graduate Program, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
  • ,
  • Po H. Lu

      Affiliations

    • Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
    • Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, United States
  • ,
  • Pablo Villablanca

      Affiliations

    • Department of Radiology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
  • ,
  • Lori L. Altshuler

      Affiliations

    • Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, United States
    • Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
  • ,
  • Michele Carter

      Affiliations

    • Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
  • ,
  • Danny Huang

      Affiliations

    • Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
  • ,
  • Nancy Edwards

      Affiliations

    • Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
    • Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, United States
  • ,
  • Jim Mintz

      Affiliations

    • Greater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, CA 90073, United States
    • Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States

Received 30 September 2005 ,Revised 2 February 2006 ,Accepted 9 February 2006.

References 

  1. Ansari KA, Loch J. Decreased myelin basic protein content of the aged human brain. Neurology. 1975;25:1045–1050
  2. Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, Ueda K, et al. Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in Lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies. Brain Res. 1999;843:53–61
  3. Barkai AI, Durkin M, Dwork AJ, Nelson HD. Autoradiographic study of iron-binding sites in the rat brain: distribution and relationship to aging.. J Neurosci Res. 1991;29:390–395
  4. Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord. 2002;16:203–212
  5. Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol Aging. 2004;25:5–18
  6. Bartzokis G. Quadratic trajectories of brain myelin content: unifying construct for neuropsychiatric disorders. Neurobiol Aging. 2004;25:49–62
  7. Bartzokis G, Aravagiri M, Oldendorf WH, Mintz J, Marder SR. Field dependent transverse relaxation rate increase may be a specific measure of tissue iron stores. Magn Reson Med. 1993;29:459–464
  8. Bartzokis G, Beckson M, Hance DB, Marx P, Foster JA, Marder SR. MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn Reson Imaging. 1997;15:29–35
  9. Bartzokis G, Cummings JL, Markham CH, Marmarelis PZ, Treciokas LJ, Tishler TA, et al. MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects. Magn Reson Imaging. 1999;17:213–222
  10. Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol. 2003;60:393–398
  11. Bartzokis G, Lu PH, Geschwind DH, Edwards N, Mintz J, Cummings JL. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch Gen Psychiatry. 2006;63:63–72
  12. Bartzokis G, Mintz J, Marx P, Osborn D, Gutkind D, Chiang F, et al. Reliability of in vivo volume measures of hippocampus and other brain structures using MRI. Magn Reson Imaging. 1993;11:993–1006
  13. Bartzokis G, Mintz J, Sultzer D, Marx P, Herzberg JS, Phelan CK, et al. In vivo MR evaluation of age-related increases in brain iron. AJNR Am J Neuroradiol. 1994;15:1129–1138
  14. Bartzokis G, Sultzer D, Cummings BJ, Holt LE, Hance DB, Henderson VW, et al. In vivo evaluation of brain iron in Alzheimer's disease and normal controls using magnetic resonance imaging. Arch Gen Psychiatry. 2000;57:47–53
  15. Bartzokis G, Sultzer D, Lu PH, Nuechterlein KH, Mintz J, Cummings J. Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer's disease. Neurobiol Aging. 2004;25:843–851
  16. Bartzokis G, Tishler TA, Shin I-S, Lu PH, Cummings JL. Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. In:  LeVine S,  Connor J,  Schipper H editor. Redox-active metals in neurological disorders. 1012:New York: Ann NY Acad Sci; 2004;p. 224–236
  17. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis. 2004;6:367–377discussion 443-449
  18. Beard JL, Connor JR. Iron status and neural functioning. Annu Rev Nutr. 2003;23:41–58
  19. Berlet HH, Llzenhofer H, Echtenacher B, Volk B. Old age alters density of myelin isolated from human brain. Exp Brain Res. 1982;(Suppl 5:):167–174
  20. Berlet HH, Volk B. Studies of human myelin proteins during old age. Mech Ageing Dev. 1980;14:211–222
  21. Berlin D, Chong G, Chertkow H, Bergman H, Phillips NA, Schipper HM. Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD and MCI. Neurobiol Aging. 2004;25:465–474
  22. Borten O, Liberman A, Tuchweber B, Chevalier S, Ferland G, Schipper HM. Effects of dietary restriction and metal supplementation on the accumulation of iron-laden glial inclusions in the aging rat hippocampus. Biogerontology. 2004;5:81–88
  23. Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, Bohl J. Pattern of brain destruction in Parkinson's and Alzheimer's diseases. J Neural Transm. 1996;103:455–490
  24. Brown LR, Harris DA. Copper and zinc cause delivery of the prion protein from the plasma membrane to a subset of early endosomes and the golgi. J Neurochem. 2003;87:353–363
  25. Bulte JW, Miller GF, Vymazal J, Brooks RA, Frank JA. Hepatic hemosiderosis in non-human primates: quantification of liver iron using different field strengths. Magn Reson Med. 1997;37:530–536
  26. Burt MJ, George PM, Upton JD, Collett JA, Frampton CM, Chapman TM, et al. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut. 1998;43:830–836
  27. Bush AI. The metallobiology of Alzheimer's disease. Trends Neurosci. 2003;26:207–214
  28. Candore G, Licastro F, Chiappelli M, Franceschi C, Lio D, Rita Balistreri C, et al. Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer's disease patients from northern Italy. Mech Ageing Dev. 2003;124:525–528
  29. Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988;p. Pages
  30. Colosimo C, Hughes AJ, Kilford L, Lees AJ. Lewy body cortical involvement may not always predict dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2003;74:852–856
  31. Combarros O, Garcia-Roman M, Fontalba A, Fernandez-Luna JL, Llorca J, Infante J, et al. Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease. Dement Geriatr Cogn Disord. 2003;15:151–154
  32. Connor JR, Menzies SL. Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience. 1990;34:265–271
  33. Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. Glia. 1996;17:83–93
  34. Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet. 1991;337:1304–1308[Published erratum appears in Lancet 1991 Jun 29;337(8757):1618, see comments]
  35. de los Monteros AE, Korsak RA, Tran T, Vu D, de Vellis J, Edmond J. Dietary iron and the integrity of the developing rat brain: a study with the artificially-reared rat pup. Cell Mol Biol (Noisy-le-grand). 2000;46:501–515
  36. Deibel MA, Ehmann WD, Markesbery WR. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. J Neurol Sci. 1996;143:137–142
  37. Dekker MC, Giesbergen PC, Njajou OT, van Swieten JC, Hofman A, Breteler MM, et al. Mutations in the hemochromatosis gene (HFE), Parkinson's disease and Parkinsonism. Neurosci Lett. 2003;348:117–119
  38. Demarquay G, Setiey A, Morel Y, Trepo C, Chazot G, Broussolle E. Clinical report of three patients with hereditary hemochromatosis and movement disorders. Mov Disord. 2000;15:1204–1209
  39. Dickson DW, Wertkin A, Kress Y, Ksiezak-Reding H, Yen SH. Ubiquitin immunoreactive structures in normal human brains. Distribution and developmental aspects. Lab Invest. 1990;63:87–99
  40. Dobson J. Investigation of age-related variations in biogenic magnetite levels in the human hippocampus. Exp Brain Res. 2002;144:122–126
  41. Dobson J. Magnetic iron compounds in neurological disorders. Ann NY Acad Sci. 2004;1012:183–192
  42. Dwork AJ. Effects of diet and development upon the uptake and distribution of cerebral iron. J Neurol Sci. 1995;134(Suppl):45–51
  43. Dwork AJ, Lawler G, Zybert PA, Durkin M, Osman M, Willson N, et al. An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Res. 1990;518:31–39
  44. Erb GL, Osterbur DL, LeVine SM. The distribution of iron in the brain: a phylogenetic analysis using iron histochemistry.. Brain Res Dev Brain Res. 1996;93:120–128
  45. Finefrock AE, Bush AI, Doraiswamy PM. Current status of metals as therapeutic targets in Alzheimer's disease. J Am Geriatr Soc. 2003;51:1143–1148
  46. Fleming DJ, Jacques PF, Massaro JM, D’Agostino RB, Wilson PW, Wood RJ. Aspirin intake and the use of serum ferritin as a measure of iron status. Am J Clin Nutr. 2001;74:219–226
  47. Fleming J, Joshi JG. Ferritin: isolation of aluminium–ferritin complex from brain. Proc Natl Acad Sci USA. 1987;84:7866–7870
  48. Fleming JT, Joshi JG. Ferritin: the role of aluminum in ferritin function. Neurobiol Aging. 1991;12:413–418
  49. Floyd RA, Carney JM. The role of metal ions in oxidative processes and aging. Toxicol Ind Health. 1993;9:197–214
  50. Francois C, Nguyen-Legros J, Percheron G. Topographical and cytological localization of iron in rat and monkey brains. Brain Res. 1981;215:317–322
  51. Fratiglioni L, Launer LJ, Andersen K, Breteler MM, Copeland JR, Dartigues JF, et al. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology. 2000;54:S10–S15
  52. Friedman A. Old-onset Parkinson's disease compared with young-onset disease: clinical differences and similarities. Acta Neurol Scand. 1994;89:258–261
  53. Gerber MR, Connor JR. Do oligodendrocytes mediate iron regulation in the human brain?. Ann Neurol. 1989;26:95–98
  54. Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B. Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem. 2002;277:16116–16123
  55. Good PF, Perl DP, Bierer LM, Schmeidler J. Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer's disease: a laser microprobe (lamma) study. Ann Neurol. 1992;31:286–292
  56. Goodman L. Alzheimer's disease: a clinico-pathologic analysis of 23 cases with a theory on pathogenesis. J Nerv Ment Dis. 1953;118:97–130
  57. Gould RM, Freund CM, Palmer F, Feinstein DL. Messenger RNAs located in myelin sheath assembly sites. J Neurochem. 2000;75:1834–1844
  58. Griffiths PD, Dobson BR, Jones GR, Clarke DT. Iron in the basal ganglia in Parkinson's disease. An in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy. Brain. 1999;122:667–673
  59. Grundke-Iqbal I, Fleming J, Tung YC, Lassmann H, Iqbal K, Joshi JG. Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neuropathol (Berl). 1990;81:105–110
  60. Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958;3:41–51
  61. Halliwell B, Gutteridge JMC. Iron as biological pro-oxidant. ISI Atlas Sci Biochem. 1988;1:48–52
  62. He L, Lu XY, Jolly AF, Eldridge AG, Watson SJ, Jackson PK, et al. Spongiform degeneration in mahoganoid mutant mice. Science. 2003;299:710–712
  63. Hilditch-Maguire P, Trettel F, Passani LA, Auerbach A, Persichetti F, MacDonald ME. Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet. 2000;9:2789–2797
  64. Hill JM, Switzer RC. The regional distribution and cellular localization of iron in the rat brain. Neuroscience. 1984;11:595–603
  65. Hirose W, Ikematsu K, Tsuda R. Age-associated increases in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Leg Med (Tokyo). 2003;5(Suppl 1):S360–S366
  66. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, et al. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem. 2005;280:20978–20986
  67. Hulet SW, Menzies S, Connor JR. Ferritin binding in the developing mouse brain follows a pattern similar to myelination and is unaffected by the jimpy mutation. Dev Neurosci. 2002;24:208–213
  68. Joshi JG, Sczekan SR, Fleming JT. Ferritin–a general metal detoxicant. Biol Trace Elem Res. 1989;21:105–110
  69. Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron. 2003;37:899–909
  70. Ke Y, Ming Qian Z. Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol. 2003;2:246–253
  71. Klintworth GK. Huntington's chorea—morphologic contributions of a century. In:  Barbeau A,  Paulson GW,  Chase TN editor. Advances in neurology, v1: Huntington's chorea, 1872–1972. Raven Press: New York; 1973;p. 353–368
  72. Kotzbauer PT, Trojanowsk JQ, Lee VM. Lewy body pathology in Alzheimer's disease. J Mol Neurosci. 2001;17:225–232
  73. Kraemer HC, Yesavage JA, Taylor JL, Kupfer D. How can we learn about developmental processes from cross-sectional studies, or can we?. Am J Psychiatry. 2000;157:163–171
  74. Lamantia AS, Rakic P. Cytological and quantitative characteristics of four cerebral commissures in the rhesus monkey. J Comp Neurol. 1990;291:520–537
  75. LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27:209–214
  76. LeVine SM, Macklin WB. Iron-enriched oligodendrocytes: a reexamination of their spatial distribution. J Neurosci Res. 1990;26:508–512
  77. Lobo A, Launer LJ, Fratiglioni L, Andersen K, Di Carlo A, Breteler MM, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology. 2000;54:S4–S9
  78. Marner L, Nyengaard JR, Tang Y, Pakkenberg B. Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol. 2003;462:144–152
  79. Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L. Incidence of AD may decline in the early 90s for men, later for women: the Cache County Study. Neurology. 2002;58:209–218
  80. Mitrofanis J, Guillery RW. New views of the thalamic reticular nucleus in the adult and the developing brain. Trends Neurosci. 1993;16:240–245
  81. Moalem S, Percy ME, Andrews DF, Kruck TP, Wong S, Dalton AJ, et al. Are hereditary hemochromatosis mutations involved in Alzheimer disease?. Am J Med Genet. 2000;93:58–66
  82. Morris CM, Candy JM, Oakley AE, Bloxham CA, Edwardson JA. Histochemical distribution of non-haem iron in the human brain. Acta Anat (Basel). 1992;144:235–257
  83. Neumann M, Adler S, Schluter O, Kremmer E, Benecke R, Kretzschmar HA. Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. Acta Neuropathol (Berl). 2000;100:568–574
  84. Newman MB, Arendash GW, Shytle RD, Bickford PC, Tighe T, Sanberg PR. Nicotine's oxidative and antioxidant properties in CNS. Life Sci. 2002;71:2807–2820
  85. Octave J-N, Schneider Y-J, Trouet A, Crichton RR. Iron uptake and utilization by mammalian cells. I. Cellular uptake of transferrin and iron. Trends Biochem Sci. 1983;8:217–220
  86. Orth M, Schapira AH. Mitochondria and degenerative disorders. Am J Med Genet. 2001;106:27–36
  87. Ozawa H, Nishida A, Mito T, Takashima S. Development of ferritin-containing cells in the pons and human brain. Brain Dev. 1994;16:92–95
  88. Ozawa H, Nishida A, Mito T, Takashima S. Development of ferritin-positive cells in cerebrum of human brain. Pediatr Neurol. 1994;10:44–48
  89. Pandya DN, Seltzer B. The topography of commissural fibers. Two hemispheres-one brain: functions of the corpus callosum: Alan R. Liss, Inc., 1986. p. 47–73.
  90. Pantelatos A, Fornadi F. Clinical features and medical treatment of Parkinson's disease in patient groups selected in accordance with age at onset. Adv Neurol. 1993;60:690–697
  91. Peters A, Sethares C. Aging and the myelinated fibers in prefrontal cortex and corpus callosum of the monkey. J Comp Neurol. 2002;442:277–291
  92. Piao YS, Hayashi S, Hasegawa M, Wakabayashi K, Yamada M, Yoshimoto M, et al. Co-localization of alpha-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration. Acta Neuropathol (Berl). 2001;101:285–293
  93. Pinero DJ, Li NQ, Connor JR, Beard JL. Variations in dietary iron alter brain iron metabolism in developing rats. J Nutr. 2000;130:254–263
  94. Prasher VP, Gosling P, Blair J. Role of iron in Alzheimer-type dementia in Down syndrome. Int J Geriatr Psychiatry. 1998;13:818–819
  95. Price D, Joshi JG. Ferritin: a zinc detoxicant and a zinc ion donor. Proc Natl Acad Sci USA. 1982;79:3116–3119
  96. Pulliam JF, Jennings CD, Kryscio RJ, Davis DG, Wilson D, Montine TJ, et al. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with ApoE. Am J Med Genet. 2003;119B:48–53
  97. Quintana C, Bellefqih S, Laval JY, Guerquin-Kern JL, Wu TD, Avila J, et al. Study of the localization of iron, ferritin, and hemosiderin in Alzheimer's disease hippocampus by analytical microscopy at the subcellular level. J Struct Biol. 2006;153:42–54
  98. Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004;25:641–650
  99. Rajan KS, Colburn RW, Davis JM. Distribution of metal ions in the subcellular fractions of several rat brain areas. Life Sci. 1976;18:423–431
  100. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, et al. Transition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains. J Neurochem. 1989;52:515–520
  101. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60:1685–1691
  102. Robson KJ, Lehmann DJ, Wimhurst VL, Livesey KJ, Combrinck M, Merryweather-Clarke AT, et al. Synergy between the c2 allele of transferrin and the c282y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease. J Med Genet. 2004;41:261–265
  103. Rosenberg CK, Cummings TJ, Saunders AM, Widico C, McIntyre LM, Hulette CM. Dementia with Lewy bodies and Alzheimer's disease. Acta Neuropathol (Berl). 2001;102:621–626
  104. Saito Y, Kawai M, Inoue K, Sasaki R, Arai H, Nanba E, et al. Widespread expression of alpha-synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome with protracted clinical course. J Neurol Sci. 2000;177:48–59
  105. Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A, Tagliabue J, et al. The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease. Neurobiol Aging. 2001;22:563–568
  106. Sanyal B, Polak PE, Szuchet S. Differential expression of the heavy-chain ferritin gene in non-adhered and adhered oligodendrocytes. J Neurosci Res. 1996;46:187–197
  107. Schipper HM. Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev. 2004;3:265–301
  108. Schupf N, Pang D, Patel BN, Silverman W, Schubert R, Lai F, et al. Onset of dementia is associated with age at menopause in women with Down's syndrome. Ann Neurol. 2003;54:433–438
  109. Shin RW, Kruck TP, Murayama H, Kitamoto T. A novel trivalent cation chelator feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease. Brain Res. 2003;961:139–146
  110. Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA. 1997;94:9866–9868
  111. Smith SR, Cooperman S, Lavaute T, Tresser N, Ghosh M, Meyron-Holtz E, et al. Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies. Ann NY Acad Sci. 2004;1012:65–83
  112. Sorond FA, Ratan RR. Ironing-out mechanisms of neuronal injury under hypoxic-ischemic conditions and potential role of iron chelators as neuroprotective agents. Antioxid Redox Signal. 2000;2:421–436
  113. Thompson CM, Markesbery WR, Ehmann WD, Mao YX, Vance DE. Regional brain trace-element studies in Alzheimer's disease. Neurotoxicology. 1988;9:1–7
  114. Turnbull S, Tabner BJ, Brown DR, Allsop D. Generation of hydrogen peroxide from mutant forms of the prion protein fragment prp121–231. Biochemistry (Mosc). 2003;42:7675–7681
  115. Vymazal J, Brooks RA, Baumgarner C, Tran V, Katz D, Bulte JW, et al. The relation between brain iron and NMR relaxation times: an in vitro study. Magn Reson Med. 1996;35:56–61
  116. Vymazal J, Brooks RA, Patronas N, Hajek M, Bulte JW, Di Chiro G. Magnetic resonance imaging of brain iron in health and disease. J Neurol Sci. 1995;134(Suppl):19–26
  117. Vymazal J, Hajek M, Patronas N, Giedd JN, Bulte JW, Baumgarner C, et al. The quantitative relation between T1-weighted and T2-weighted MRI of normal gray matter and iron concentration. J Magn Reson Imaging. 1995;5:554–560
  118. Vymazal J, Zak O, Bulte JW, Aisen P, Brooks RA. T1 and T2 of ferritin solutions: effect of loading factor. Magn Reson Med. 1996;36:61–65
  119. Wang XS, Lee S, Simmons Z, Boyer P, Scott K, Liu W, et al. Increased incidence of the HFE mutation in amyotrophic lateral sclerosis and related cellular consequences. J Neurol Sci. 2004;227:27–33
  120. Watt NT, Hooper NM. The prion protein and neuronal zinc homeostasis. Trends Biochem Sci. 2003;28:406–410
  121. Whitfield JB, Treloar S, Zhu G, Powell LW, Martin NG. Relative importance of female-specific and non-female-specific effects on variation in iron stores between women. Br J Haematol. 2003;120:860–866
  122. Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F, et al. Iron (iii) induces aggregation of hyperphosphorylated tau and its reduction to iron (ii) reverses the aggregation: Implications in the formation of neurofibrillary tangles of Alzheimer's disease. J Neurochem. 2002;82:1137–1147
  123. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5:863–873

PII: S0197-4580(06)00051-0

doi: 10.1016/j.neurobiolaging.2006.02.005

Neurobiology of Aging
Volume 28, Issue 3 , Pages 414-423 , March 2007