Iron, aging, and neurodegeneration

Metals

Volumn 5, Issue 4, 2015, Pages 2070-2092

  Angelova, Dafina M ^a   Brown, David R ^a  

^a University of Bath   (United Kingdom)

Author keywords

Alzheimer s disease; Amyloid; Ferrireductase; Microglia; Parkinson s disease; Prion; Synuclein; Transmissible spongiform encephalopathy

Indexed keywords

EID: 84946849908     PISSN: None     EISSN: 20754701     Source Type: Journal    
DOI: 10.3390/met5042070     Document Type: Review

References (159)

1. Oliveira, B.F.; Nogueira-Machado, J.A.; Chaves, M.M. The role of oxidative stress in the aging process. Sci. World J. 2010, 10, 1121-1128.
2. Cobb, C.A.; Cole, M.P. Oxidative and nitrative stress in neurodegeneration. Neurobiol. Dis. 2015, doi:10.1016/j.nbd.2015.04.020.
3. Phillipson, O.T. Management of the aging risk factor for Parkinson's disease. Neurobiol. Aging 2014, 35, 847-857.
4. Mao, P.; Reddy, P.H. Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: Implications for early intervention and therapeutics. Biochim. Biophys. Acta 2011, 1812, 1359-1370.
5. Ward, R.J.; Zucca, F.A.; Duyn, J.H.; Crichton, R.R.; Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014, 13, 1045-1060.
6. Crichton, R.R.; Ward, R.J. Iron homeostasis. Met. Ions Biol. Syst. 1998, 35, 633-665.
7. Drennan, C.L.; Peters, J.W. Surprising cofactors in metalloenzymes. Curr. Opin. Struct. Biol. 2003, 13, 220-226.
8. Dunn, L.L.; Rahmanto, Y.S.; Richardson, D.R. Iron uptake and metabolism in the new millennium. Trends Cell Biol. 2007, 17, 93-100.
9. Sargent, P.J.; Farnaud, S.; Evans, R.W. Structure/function overview of proteins involved in iron storage and transport. Curr. Med. Chem. 2005, 12, 2683-2693.
10. Skjorringe, T.; Burkhart, A.; Johnsen, K.B.; Moos, T. Divalent metal transporter 1 (DMT1) in the brain: Implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology. Front. Mol. Neurosci. 2015, doi:10.3389/fnmol.2015.00019.
11. Koorts, A.M.; Viljoen, M. Ferritin and ferritin isoforms II: Protection against uncontrolled cellular proliferation, oxidative damage and inflammatory processes. Arch. Physiol. Biochem. 2007, 113, 55-64.
12. Winter, W.E.; Bazydlo, L.A.; Harris, N.S. The molecular biology of human iron metabolism. Lab. Med. 2014, 45, 92-102.
13. Hider, R.C.; Kong, X. Iron speciation in the cytosol: An overview. Dalton Trans. 2013, 42, 3220-3229.
14. Kruszewski, M. Labile iron pool: The main determinant of cellular response to oxidative stress. Mutat. Res. 2003, 531, 81-92.
15. Koeppen, A.H. A brief history of brain iron research. J. Neurol. Sci. 2003, 207, 95-97.
16. Koeppen, A.H. The history of iron in the brain. J. Neurol. Sci. 1995, 134, 1-9.
17. Gotz, M.E.; Double, K.; Gerlach, M.; Youdim, M.B.; Riederer, P. The relevance of iron in the pathogenesis of Parkinson's disease. Ann. N. Y. Acad. Sci. 2004, 1012, 193-208.
18. Burdo, J.R.; Martin, J.; Menzies, S.L.; Dolan, K.G.; Romano, M.A.; Fletcher, R.J.; Garrick, M.D.; Garrick, L.M.; Connor, J.R. Cellular distribution of iron in the brain of the belgrade rat. Neuroscience 1999, 93, 1189-1196.
19. Connor, J.R.; Boeshore, K.L.; Benkovic, S.A.; Menzies, S.L. Isoforms of ferritin have a specific cellular distribution in the brain. J. Neurosci. Res. 1994, 37, 461-465.
20. Moos, T.; Morgan, E.H. The significance of the mutated divalent metal transporter (DMT1) on iron transport into the belgrade rat brain. J. Neurochem. 2004, 88, 233-245.
21. Zecca, L.; Casella, L.; Albertini, A.; Bellei, C.; Zucca, F.A.; Engelen, M.; Zadlo, A.; Szewczyk, G.; Zareba, M.; Sarna, T. Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson's disease. J. Neurochem. 2008, 106, 1866-1875.
22. Zucca, F.A.; Giaveri, G.; Gallorini, M.; Albertini, A.; Toscani, M.; Pezzoli, G.; Lucius, R.; Wilms, H.; Sulzer, D.; Ito, S.; et al. The neuromelanin of human substantia nigra: Physiological and pathogenic aspects. Pigment Cell Res. 2004, 17, 610-617.
23. Zecca, L.; Gallorini, M.; Schunemann, V.; Trautwein, A.X.; Gerlach, M.; Riederer, P.; Vezzoni, P.; Tampellini, D. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: Consequences for iron storage and neurodegenerative processes. J. Neurochem. 2001, 76, 1766-1773.
24. Hallgren, B.; Sourander, P. The effect of age on the non-haemin iron in the human brain. J. Neurochem. 1958, 3, 41-51.
25. Faucheux, B.A.; Bonnet, A.M.; Agid, Y.; Hirsch, E.C. Blood vessels change in the mesencephalon of patients with Parkinson's disease. Lancet 1999, 353, 981-982.
26. Brun, A.; Englund, E. Brain changes in dementia of Alzheimer's type relevant to new imaging diagnostic methods. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1986, 10, 297-308.
27. Pandolfo, M. Friedreich's ataxia: Clinical aspects and pathogenesis. Semin. Neurol. 1999, 19, 311-321.
28. Campuzano, V.; Montermini, L.; Molto, M.D.; Pianese, L.; Cossee, M.; Cavalcanti, F.; Monros, E.; Rodius, F.; Duclos, F.; Monticelli, A.; et al. Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996, 271, 1423-1427.
29. Napier, I.; Ponka, P.; Richardson, D.R. Iron trafficking in the mitochondrion: Novel pathways revealed by disease. Blood 2005, 105, 1867-1874.
30. Tsai, C.L.; Barondeau, D.P. Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex. Biochemistry 2010, 49, 9132-9139.
31. Jiralerspong, S.; Liu, Y.; Montermini, L.; Stifani, S.; Pandolfo, M. Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol. Dis. 1997, 4, 103-113.
32. Boddaert, N.; Sang, K.H.L.Q.; Rotig, A.; Leroy-Willig, A.; Gallet, S.; Brunelle, F.; Sidi, D.; Thalabard, J.C.; Munnich, A.; Cabantchik, Z.I. Selective iron chelation in friedreich ataxia: Biologic and clinical implications. Blood 2007, 110, 401-408.
33. Levi, S.; Rovida, E. Neuroferritinopathy: From ferritin structure modification to pathogenetic mechanism. Neurobiol. Dis. 2015, doi:10.1016/j.nbd.2015.02.007.
34. Levi, S.; Finazzi, D. Neurodegeneration with brain iron accumulation: Update on pathogenic mechanisms. Front. Pharmacol. 2014, doi:10.3389/fphar.2014.00099.
35. Curtis, A.R.; Fey, C.; Morris, C.M.; Bindoff, L.A.; Ince, P.G.; Chinnery, P.F.; Coulthard, A.; Jackson, M.J.; Jackson, A.P.; McHale, D.P.; et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet. 2001, 28, 350-354.
36. Baraibar, M.A.; Muhoberac, B.B.; Garringer, H.J.; Hurley, T.D.; Vidal, R. Unraveling of the e-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration. J. Biol. Chem. 2010, 285, 1950-1956.
37. Mancuso, M.; Davidzon, G.; Kurlan, R.M.; Tawil, R.; Bonilla, E.; Mauro, S.D.; Powers, J.M. Hereditary ferritinopathy: A novel mutation, its cellular pathology, and pathogenetic insights. J. Neuropathol. Exp. Neurol. 2005, 64, 280-294.
38. Barbeito, A.G.; Garringer, H.J.; Baraibar, M.A.; Gao, X.; Arredondo, M.; Nunez, M.T.; Smith, M.A.; Ghetti, B.; Vidal, R. Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. J. Neurochem. 2009, 109, 1067-1078.
39. Burn, J.; Chinnery, P.F. Neuroferritinopathy. Semin. Pediatr. Neurol. 2006, 13, 176-181.
40. Hayflick, S.J. Unraveling the hallervorden-spatz syndrome: Pantothenate kinase-associated neurodegeneration is the name. Curr. Opin. Pediatr. 2003, 15, 572-577.
41. Zhou, B.; Westaway, S.K.; Levinson, B.; Johnson, M.A.; Gitschier, J.; Hayflick, S.J. A novel pantothenate kinase gene (pank2) is defective in hallervorden-spatz syndrome. Nat. Genet. 2001, 28, 345-349.
42. Zeidman, L.A.; Pandey, D.K. Declining use of the hallervorden-spatz disease eponym in the last two decades. J. Child Neurol. 2012, 27, 1310-1315.
43. Hogarth, P. Neurodegeneration with brain iron accumulation: Diagnosis and management. J. Mov. Disord. 2015, 8, 1-13.
44. Szumowski, J.; Bas, E.; Gaarder, K.; Schwarz, E.; Erdogmus, D.; Hayflick, S. Measurement of brain iron distribution in hallevorden-spatz syndrome. J. Magn. Reson. Imaging 2010, 31, 482-489.
45. Gordon, N. Pantothenate kinase-associated neurodegeneration (hallervorden-spatz syndrome). Eur. J. Paediatr. Neurol. 2002, 6, 243-247.
46. Hayflick, S.J.; Hogarth, P. As iron goes, so goes disease? Haematologica 2011, 96, 1571-1572.
47. Ghosh, M.C.; Zhang, L.; Rouault, T.A. Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins. Neurobiol. Dis. 2015, doi:10.1016/j.nbd.2015.02.026.
48. Rouault, T.A. Mammalian iron-sulphur proteins: Novel insights into biogenesis and function. Nat. Rev. Mol. Cell Biol. 2015, 16, 45-55.
49. Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science 2002, 297, 353-356.
50. Lombardo, S.; Maskos, U. Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment. Neuropharmacology 2015, 96, 255-262.
51. Guerreiro, R.; Hardy, J. Genetics of Alzheimer's disease. Neurotherapeutics 2014, 11, 732-737.
52. Hardy, J.; Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 1991, 12, 383-388.
53. Iqbal, K.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I. Tau in alzheimer disease and related tauopathies. Curr. Alzheimer Res. 2010, 7, 656-664.
54. Barbato, C.; Canu, N.; Zambrano, N.; Serafino, A.; Minopoli, G.; Ciotti, M.T.; Amadoro, G.; Russo, T.; Calissano, P. Interaction of Tau with Fe65 links tau to APP. Neurobiol. Dis. 2005, 18, 399-408.
55. Nalivaeva, N.N.; Turner, A.J. The amyloid precursor protein: A biochemical enigma in brain development, function and disease. FEBS Lett. 2013, 587, 2046-2054.
56. Hesse, L.; Beher, D.; Masters, C.L.; Multhaup, G. The beta A4 amyloid precursor protein binding to copper. FEBS Lett. 1994, 349, 109-116.
57. Spoerri, L.; Vella, L.J.; Pham, C.L.; Barnham, K.J.; Cappai, R. The amyloid precursor protein copper binding domain histidine residues 149 and 151 mediate App stability and metabolism. J. Biol. Chem. 2012, 287, 26840-26853.
58. Dahms, S.O.; Konnig, I.; Roeser, D.; Guhrs, K.H.; Mayer, M.C.; Kaden, D.; Multhaup, G.; Than, M.E. Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. J. Mol. Biol. 2012, 416, 438-452.
59. Ebrahimi, K.H.; Dienemann, C.; Hoefgen, S.; Than, M.E.; Hagedoorn, P.L.; Hagen, W.R. The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain. PLoS ONE 2013, doi:10.1371/journal.pone.0072177.
60. Duce, J.A.; Tsatsanis, A.; Cater, M.A.; James, S.A.; Robb, E.; Wikhe, K.; Leong, S.L.; Perez, K.; Johanssen, T.; Greenough, M.A.; et al. Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 2010, 142, 857-867.
61. Wong, B.X.; Tsatsanis, A.; Lim, L.Q.; Adlard, P.A.; Bush, A.I.; Duce, J.A. β-amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS ONE 2014, doi:10.1371/journal.pone.0114174.
62. Borchardt, T.; Camakaris, J.; Cappai, R.; Masters, C.L.; Beyreuther, K.; Multhaup, G. Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion. Biochem. J. 1999, 344, 461-467.
63. Baumkotter, F.; Schmidt, N.; Vargas, C.; Schilling, S.; Weber, R.; Wagner, K.; Fiedler, S.; Klug, W.; Radzimanowski, J.; Nickolaus, S.; et al. Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain. J. Neurosci. 2014, 34, 11159-11172.
64. Garzon-Rodriguez, W.; Yatsimirsky, A.K.; Glabe, C.G. Binding of Zn(II), Cu(II), and Fe(II) ions to Alzheimer's A beta peptide studied by fluorescence. Bioorg. Med. Chem. Lett. 1999, 9, 2243-2248.
65. Bush, A.I.; Pettingell, W.H., Jr.; Paradis, M.D.; Tanzi, R.E. Modulation of a beta adhesiveness and secretase site cleavage by zinc. J. Biol. Chem. 1994, 269, 12152-12158.
66. Streltsov, V.A.; Titmuss, S.J.; Epa, V.C.; Barnham, K.J.; Masters, C.L.; Varghese, J.N. The structure of the amyloid-beta peptide high-affinity copper II binding site in alzheimer disease. Biophys. J. 2008, 95, 3447-3456.
67. Cherny, R.A.; Atwood, C.S.; Xilinas, M.E.; Gray, D.N.; Jones, W.D.; McLean, C.A.; Barnham, K.J.; Volitakis, I.; Fraser, F.W.; Kim, Y.; et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001, 30, 665-676.
68. Faux, N.G.; Ritchie, C.W.; Gunn, A.; Rembach, A.; Tsatsanis, A.; Bedo, J.; Harrison, J.; Lannfelt, L.; Blennow, K.; Zetterberg, H.; et al. PBT2 rapidly improves cognition in Alzheimer's disease: Additional phase II analyses. J. Alzheimers Dis. 2010, 20, 509-516.
69. Ayton, S.; Lei, P.; Bush, A.I. Biometals and their therapeutic implications in Alzheimer's disease. Neurotherapeutics 2015, 12, 109-120.
70. Dedman, D.J.; Treffry, A.; Candy, J.M.; Taylor, G.A.; Morris, C.M.; Bloxham, C.A.; Perry, R.H.; Edwardson, J.A.; Harrison, P.M. Iron and aluminium in relation to brain ferritin in normal individuals and Alzheimer's-disease and chronic renal-dialysis patients. Biochem. J. 1992, 287, 509-514.
71. Bartzokis, G.; Sultzer, D.; Mintz, J.; Holt, L.E.; Marx, P.; Phelan, C.K.; Marder, S.R. In vivo evaluation of brain iron in Alzheimer's disease and normal subjects using mri. Biol. Psychiatry 1994, 35, 480-487.
72. Castellani, R.J.; Honda, K.; Zhu, X.; Cash, A.D.; Nunomura, A.; Perry, G.; Smith, M.A. Contribution of redox-active iron and copper to oxidative damage in alzheimer disease. Ageing Res. Rev. 2004, 3, 319-326.
73. Bonda, D.J.; Lee, H.G.; Blair, J.A.; Zhu, X.; Perry, G.; Smith, M.A. Role of metal dyshomeostasis in Alzheimer's disease. Metallomics 2011, 3, 267-270.
74. Ayton, S.; Faux, N.G.; Bush, A.I.; Alzheimer's Disease Neuroimaging Initiative. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat. Commun. 2015, doi:10.1038/ncomms7760.
75. Rottkamp, C.A.; Raina, A.K.; Zhu, X.; Gaier, E.; Bush, A.I.; Atwood, C.S.; Chevion, M.; Perry, G.; Smith, M.A. Redox-active iron mediates amyloid-beta toxicity. Free Radic. Biol. Med. 2001, 30, 447-450.
76. Stephenson, D.T.; Clemens, J.A. In vivo effects of beta-amyloid implants in rodents: Lack of potentiation of damage associated with transient global forebrain ischemia. Brain Res. 1992, 586, 235-246.
77. Friedland-Leuner, K.; Stockburger, C.; Denzer, I.; Eckert, G.P.; Muller, W.E. Mitochondrial dysfunction: Cause and consequence of Alzheimer's disease. Prog. Mol. Biol. Transl. Sci. 2014, 127, 183-210.
78. Atamna, H. Heme, iron, and the mitochondrial decay of ageing. Ageing Res. Rev. 2004, 3, 303-318.
79. Hirai, K.; Aliev, G.; Nunomura, A.; Fujioka, H.; Russell, R.L.; Atwood, C.S.; Johnson, A.B.; Kress, Y.; Vinters, H.V.; Tabaton, M.; et al. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 2001, 21, 3017-3023.
80. Perry, G.; Taddeo, M.A.; Petersen, R.B.; Castellani, R.J.; Harris, P.L.; Siedlak, S.L.; Cash, A.D.; Liu, Q.; Nunomura, A.; Atwood, C.S.; et al. Adventiously-bound redox active iron and copper are at the center of oxidative damage in alzheimer disease. Biometals 2003, 16, 77-81.
81. Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. α-synuclein in lewy bodies. Nature 1997, 388, 839-840.
82. Saito, Y.; Ruberu, N.N.; Sawabe, M.; Arai, T.; Kazama, H.; Hosoi, T.; Yamanouchi, H.; Murayama, S. Lewy body-related α-synucleinopathy in aging. J. Neuropathol. Exp. Neurol. 2004, 63, 742-749.
83. Goedert, M. α-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2001, 2, 492-501.
84. Dickson, D.W. Parkinson's disease and parkinsonism: Neuropathology. Cold Spring Harb. Perspect. Med. 2012, doi:10.1101/cshperspect.a009258.
85. Dexter, D.T.; Wells, F.R.; Agid, F.; Agid, Y.; Lees, A.J.; Jenner, P.; Marsden, C.D. Increased nigral iron content in postmortem parkinsonian brain. Lancet 1987, 2, 1219-1220.
86. Singleton, A.B.; Farrer, M.J.; Bonifati, V. The genetics of Parkinson's disease: Progress and therapeutic implications. Mov. Disord. 2013, 28, 14-23.
87. Leenders, K.L.; Oertel, W.H. Parkinson's disease: Clinical signs and symptoms, neural mechanisms, positron emission tomography, and therapeutic interventions. Neural Plast. 2001, 8, 99-110.
88. Cenci, M.A. Presynaptic mechanisms of L-DOPA-induced dyskinesia: The findings, the debate, and the therapeutic implications. Front Neurol 2014, doi:10.3389/fneur.2014.00242.
89. Dexter, D.T.; Carayon, A.; Javoy-Agid, F.; Agid, Y.; Wells, F.R.; Daniel, S.E.; Lees, A.J.; Jenner, P.; Marsden, C.D. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991, 114, 1953-1975.
90. Hirsch, E.C.; Brandel, J.P.; Galle, P.; Javoy-Agid, F.; Agid, Y. Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: An X-ray microanalysis. J. Neurochem. 1991, 56, 446-451.
91. Tofaris, G.K.; Revesz, T.; Jacques, T.S.; Papacostas, S.; Chataway, J. Adult-onset neurodegeneration with brain iron accumulation and cortical α-synuclein and tau pathology: A distinct clinicopathological entity. Arch. Neurol. 2007, 64, 280-282.
92. Pall, H.S.; Williams, A.C.; Blake, D.R.; Lunec, J.; Gutteridge, J.M.; Hall, M.; Taylor, A. Raised cerebrospinal-fluid copper concentration in Parkinson's disease. Lancet 1987, 2, 238-241.
93. Gorrell, J.M.; DiMonte, D.; Graham, D. The role of the environment in Parkinson's disease. Environ. Health Perspect. 1996, 104, 652-654.
94. Kalivendi, S.V.; Cunningham, S.; Kotamraju, S.; Joseph, J.; Hillard, C.J.; Kalyanaraman, B. α-synuclein up-regulation and aggregation during mpp+-induced apoptosis in neuroblastoma cells: Intermediacy of transferrin receptor iron and hydrogen peroxide. J. Biol. Chem. 2004, 279, 15240-15247.
95. Mandel, S.; Maor, G.; Youdim, M.B. Iron and α-synuclein in the substantia nigra of mptp-treated mice: Effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate. J. Mol. Neurosci. 2004, 24, 401-416.
96. Sengstock, G.J.; Olanow, C.W.; Menzies, R.A.; Dunn, A.J.; Arendash, G.W. Infusion of iron into the rat substantia nigra: Nigral pathology and dose-dependent loss of striatal dopaminergic markers. J. Neurosci. Res. 1993, 35, 67-82.
97. Double, K.L.; Halliday, G.M. New face of neuromelanin. J. Neural Transm. Suppl. 2006, 119-123.
98. Li, J.; Yang, J.; Zhao, P.; Li, S.; Zhang, R.; Zhang, X.; Liu, D.; Zhang, B. Neuromelanin enhances the toxicity of alpha-synuclein in SK-N-SH cells. J. Neural Transm. 2012, 119, 685-691.
99. Gerlach, M.; Riederer, P.; Double, K.L. Neuromelanin-bound ferric iron as an experimental model of dopaminergic neurodegeneration in Parkinson's disease. Parkinsonism Relat. Disord. 2008, 14, S185-S188.
100. Fasano, M.; Bergamasco, B.; Lopiano, L. Is neuromelanin changed in Parkinson's disease? Investigations by magnetic spectroscopies. J. Neural Transm. 2006, 113, 769-774.
101. Silva, B.; Faustino, P. An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim. Biophys. Acta 2015, 1852, 1347-1359.
102. Hanson, E.S.; Leibold, E.A. Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species. Gene Expr. 1999, 7, 367-376.
103. Connor, J.R.; Snyder, B.S.; Arosio, P.; Loeffler, D.A.; LeWitt, P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer's diseased brains. J. Neurochem. 1995, 65, 717-724.
104. Jinsmaa, Y.; Sullivan, P.; Gross, D.; Cooney, A.; Sharabi, Y.; Goldstein, D.S. Divalent metal ions enhance dopal-induced oligomerization of alpha-synuclein. Neurosci. Lett. 2014, 569, 27-32.
105. Li, S.W.; Lin, T.S.; Minteer, S.; Burke, W.J. 3, 4-dihydroxyphenylacetaldehyde and hydrogen peroxide generate a hydroxyl radical: Possible role in Parkinson's disease pathogenesis. Brain Res. Mol. Brain Res. 2001, 93, 1-7.
106. Davies, P.; Wang, X.; Sarell, C.J.; Drewett, A.; Marken, F.; Viles, J.H.; Brown, D.R. The synucleins are a family of redox-active copper binding proteins. Biochemistry 2010, 50, 37-47.
107. Rasia, R.M.; Bertoncini, C.W.; Marsh, D.; Hoyer, W.; Cherny, D.; Zweckstetter, M.; Griesinger, C.; Jovin, T.M.; Fernandez, C.O. Structural characterization of copper(II) binding to α-synuclein: Insights into the bioinorganic chemistry of Parkinson's disease. Proc. Natl. Acad. Sci. USA 2005, 102, 4294-4299.
108. Binolfi, A.; Rasia, R.M.; Bertoncini, C.W.; Ceolin, M.; Zweckstetter, M.; Griesinger, C.; Jovin, T.M.; Fernandez, C.O. Interaction of α-synuclein with divalent metal ions reveals key differences: A link between structure, binding specificity and fibrillation enhancement. J. Am. Chem. Soc. 2006, 128, 9893-9901.
109. Davies, P.; Moualla, D.; Brown, D.R. α-synuclein is a cellular ferrireductase. PLoS ONE 2011, doi:10.1371/journal.pone.0015814.
110. Uversky, V.N.; Li, J.; Fink, A.L. Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein. A possible molecular nk between Parkinson's disease and heavy metal exposure. J. Biol. Chem. 2001, 276, 44284-44296.
111. Wright, J.A.; Wang, X.; Brown, D.R. Unique copper-induced oligomers mediate α-synuclein toxicity. FASEB J. 2009, 23, 2384-2393.
112. Wang, X.; Moualla, D.; Wright, J.A.; Brown, D.R. Copper binding regulates intracellular α-synuclein localisation, aggregation and toxicity. J. Neurochem. 2010, 113, 704-714.
113. Levin, J.; Hogen, T.; Hillmer, A.S.; Bader, B.; Schmidt, F.; Kamp, F.; Kretzschmar, H.A.; Botzel, K.; Giese, A. Generation of ferric iron links oxidative stress to α-synuclein oligomer formation. J. Parkinson's Dis. 2011, 1, 205-216.
114. Ortega, R.; Carmona, A.; Roudeau, S.; Perrin, L.; Ducic, T.; Carboni, E.; Bohic, S.; Cloetens, P.; Lingor, P. α-synuclein over-expression induces increased iron accumulation and redistribution in iron-exposed neurons. Mol. Neurobiol. 2015, doi:10.1007/s12035-015-9146-x.
115. Prusiner, S.B. Prions. Proc. Natl. Acad. Sci. USA 1998, 95, 13363-13383.
116. Ironside, J.W.; Sutherland, K.; Bell, J.E.; McCardle, L.; Barrie, C.; Estebeiro, K.; Zeidler, M.; Will, R.G. A new variant of Creutzfeldt-Jakob disease: Neuropathological and clinical features. Cold Spring Harb. Symp. Quant. Biol. 1996, 61, 523-530.
117. Hope, J.; Reekie, L.J.; Hunter, N.; Multhaup, G.; Beyreuther, K.; White, H.; Scott, A.C.; Stack, M.J.; Dawson, M.; Wells, G.A. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature 1988, 336, 390-392.
118. Knight, R. Creutzfeldt-Jakob disease: A rare cause of dementia in elderly persons. Clin. Infect. Dis. 2006, 43, 340-346.
119. Bolton, D.C.; McKinley, M.P.; Prusiner, S.B. Identification of a protein that purifies with the scrapie prion. Science 1982, 218, 1309-1311.
120. Endo, T.; Groth, D.; Prusiner, S.B.; Kobata, A. Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein. Biochemistry 1989, 28, 8380-8388.
121. Brown, D.R.; Qin, K.; Herms, J.W.; Madlung, A.; Manson, J.; Strome, R.; Fraser, P.E.; Kruck, T.; von Bohlen, A.; Schulz-Schaeffer, W.; et al. The cellular prion protein binds copper in vivo. Nature 1997, 390, 684-687.
122. Brown, D.R.; Wong, B.S.; Hafiz, F.; Clive, C.; Haswell, S.J.; Jones, I.M. Normal prion protein has an activity like that of superoxide dismutase. Biochem. J. 1999, 344, 1-5.
123. Brown, D.R. Prion and prejudice: Normal protein and the synapse. Trends Neurosci. 2001, 24, 85-90.
124. Davies, P.; Brown, D.R. The chemistry of copper binding to PrP: Is there sufficient evidence to elucidate a role for copper in protein function? Biochem. J. 2008, 410, 237-244.
125. Brown, D.R. Metalloproteins and neuronal death. Metallomics 2010, 2, 186-194.
126. Brown, D.R. Prions and manganese: A maddening beast. Metallomics 2011, 3, 229-238.
127. Brown, D.R.; Hafiz, F.; Glasssmith, L.L.; Wong, B.S.; Jones, I.M.; Clive, C.; Haswell, S.J. Consequences of manganese replacement of copper for prion protein function and proteinase resistance. EMBO J. 2000, 19, 1180-1186.
128. Brazier, M.W.; Davies, P.; Player, E.; Marken, F.; Viles, J.H.; Brown, D.R. Manganese binding to the prion protein. J. Biol. Chem. 2008, 283, 12831-12839.
129. Davies, P.; Brown, D.R. Manganese enhances prion protein survival in model soils and increases prion infectivity to cells. PLoS ONE 2009, doi:10.1371/journal.pone.0007518.
130. Hesketh, S.; Sassoon, J.; Knight, R.; Hopkins, J.; Brown, D.R. Elevated manganese levels in blood and central nervous system occur before onset of clinical signs in scrapie and bovine spongiform encephalopathy. J. Anim. Sci. 2007, 85, 1596-1609.
131. Hesketh, S.; Sassoon, J.; Knight, R.; Brown, D.R. Elevated manganese levels in blood and CNS in human prion disease. Mol. Cell. Neurosci. 2008, 37, 590-598.
132. Thackray, A.M.; Knight, R.; Haswell, S.J.; Bujdoso, R.; Brown, D.R. Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem. J. 2002, 362, 253-258.
133. Johnson, C.J.; Gilbert, P.U.; Abrecht, M.; Baldwin, K.L.; Russell, R.E.; Pedersen, J.A.; Aiken, J.M.; McKenzie, D. Low copper and high manganese levels in prion protein plaques. Viruses 2013, 5, 654-662.
134. Singh, N.; Haldar, S.; Tripathi, A.K.; McElwee, M.K.; Horback, K.; Beserra, A. Iron in neurodegenerative disorders of protein misfolding: A case of prion disorders and Parkinson's disease. Antioxid. Redox Signal. 2014, 21, 471-484.
135. Kim, B.H.; Jun, Y.C.; Jin, J.K.; Kim, J.I.; Kim, N.H.; Leibold, E.A.; Connor, J.R.; Choi, E.K.; Carp, R.I.; Kim, Y.S. Alteration of iron regulatory proteins (IRP1 and IRP2) and ferritin in the brains of scrapie-infected mice. Neurosci. Lett. 2007, 422, 158-163.
136. Singh, A.; Mohan, M.L.; Isaac, A.O.; Luo, X.; Petrak, J.; Vyoral, D.; Singh, N. Prion protein modulates cellular iron uptake: A novel function with implications for prion disease pathogenesis. PLoS ONE 2009, doi:10.1371/journal.pone.0004468.
137. Singh, A.; Isaac, A.O.; Luo, X.; Mohan, M.L.; Cohen, M.L.; Chen, F.; Kong, Q.; Bartz, J.; Singh, N. Abnormal brain iron homeostasis in human and animal prion disorders. PLoS Pathog. 2009, doi:10.1371/journal.ppat.1000336.
138. Singh, A.; Kong, Q.; Luo, X.; Petersen, R.B.; Meyerson, H.; Singh, N. Prion protein (PrP) knock-out mice show altered iron metabolism: A functional role for PrP in iron uptake and transport. PLoS ONE 2009, doi:10.1371/journal.pone.0006115.
139. Kralovicova, S.; Fontaine, S.N.; Alderton, A.; Alderman, J.; Ragnarsdottir, K.V.; Collins, S.J.; Brown, D.R. The effects of prion protein expression on metal metabolism. Mol. Cell. Neurosci. 2009, 41, 135-147.
140. Singh, A.; Haldar, S.; Horback, K.; Tom, C.; Zhou, L.; Meyerson, H.; Singh, N. Prion protein regulates iron transport by functioning as a ferrireductase. J. Alzheimers Dis. 2013, 35, 541-552.
141. Brown, D.R. Role of microglia in age-related changes to the nervous system. Sci. World J. 2009, 9, 1061-1071.
142. Aloisi, F. Immune function of microglia. Glia 2001, 36, 165-179.
143. Streit, W.J.; Sammons, N.W.; Kuhns, A.J.; Sparks, D.L. Dystrophic microglia in the aging human brain. Glia 2004, 45, 208-212.
144. Njie, E.G.; Boelen, E.; Stassen, F.R.; Steinbusch, H.W.; Borchelt, D.R.; Streit, W.J. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging 2012, 33, 195.e1-195.e12.
145. Solito, E.; Sastre, M. Microglia function in Alzheimer's disease. Front. Pharmacol. 2012, doi:10.3389/fphar.2012.00014.
146. Schilling, T.; Eder, C. Microglial K+ channel expression in young adult and aged mice. Glia 2015, 63, 664-672.
147. Lopes, K.O.; Sparks, D.L.; Streit, W.J. Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia 2008, 56, 1048-1060.
148. Simmons, D.A.; Casale, M.; Alcon, B.; Pham, N.; Narayan, N.; Lynch, G. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease. Glia 2007, 55, 1074-1084.
149. Thomsen, M.S.; Andersen, M.V.; Christoffersen, P.R.; Jensen, M.D.; Lichota, J.; Moos, T. Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons. Neurobiol. Dis. 2015, doi:10.1016/j.nbd.2015.03.013.
150. Streit, W.J.; Xue, Q.S.; Tischer, J.; Bechmann, I. Microglial pathology. Acta Neuropathol. Commun. 2014, doi:10.1186/s40478-014-0142-6.
151. Streit, W.J.; Braak, H.; Xue, Q.S.; Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 2009, 118, 475-485.
152. Krabbe, G.; Halle, A.; Matyash, V.; Rinnenthal, J.L.; Eom, G.D.; Bernhardt, U.; Miller, K.R.; Prokop, S.; Kettenmann, H.; Heppner, F.L. Functional impairment of microglia coincides with β-amyloid deposition in mice with alzheimer-like pathology. PLoS ONE 2013, doi:10.1371/journal.pone.0060921.
153. Qiu, W.Q.; Ye, Z.; Kholodenko, D.; Seubert, P.; Selkoe, D.J. Degradation of amyloid β-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J. Biol. Chem. 1997, 272, 6641-6646.
154. DiCarlo, G.; Wilcock, D.; Henderson, D.; Gordon, M.; Morgan, D. Intrahippocampal LPS injections reduce Aβ load in APP + PS1 transgenic mice. Neurobiol. Aging 2001, 22, 1007-1012.
155. Li, M.; Pisalyaput, K.; Galvan, M.; Tenner, A.J. Macrophage colony stimulatory factor and interferon-γ trigger distinct mechanisms for augmentation of β-amyloid-induced microglia-mediated neurotoxicity. J. Neurochem. 2004, 91, 623-633.
156. Mrak, R.E.; Griffin, W.S. The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol. Aging 2001, 22, 915-922.
157. Erta, M.; Quintana, A.; Hidalgo, J. Interleukin-6, a major cytokine in the central nervous system. Int. J. Biol. Sci. 2012, 8, 1254-1266.
158. Cartier, N.; Lewis, C.A.; Zhang, R.; Rossi, F.M. The role of microglia in human disease: Therapeutic tool or target? Acta Neuropathol. 2014, 128, 363-380.
159. Prokop, S.; Miller, K.R.; Heppner, F.L. Microglia actions in Alzheimer's disease. Acta Neuropathol. 2013, 126, 461-477.