Eisen im alternden Gehirn

Zusammenfassung

Eisen ist ein essentielles Spurenelement für eine Vielzahl von Stoffwechselreaktionen des Körpers. Auch im Gehirn ist es von besonderer Bedeutung. Die Aufnahme über die Blut-Hirn-Schranke und die Verteilung und Speicherung im Gehirn ist ein streng regulierter Prozess, damit neurotoxische Effekte des Eisens verhindert werden. Im alternden Gehirn geht vermehrte Eisenspeicherung in Kortex und Basalganglien mit Einschränkungen der kognitiven und motorischen Fähigkeiten einher. Man geht außerdem davon aus, dass Eisen zu neurodegenerativen Erkrankungen des Alters wie Morbus Parkinson und Morbus Alzheimer beiträgt. Vermehrte Eisenablagerung findet sich beim Morbus Parkinson in der Substantia nigra, wo dopaminerge Neurone untergehen. Eisen fördert außerdem die α-Synuclein-Aggregation in Lewy-Körperchen und sorgt für Bildung toxischer Hydroxylradikale. Beim Morbus Alzheimer ist Eisen an der Bildung von β-Amyloid-Plaques und Neurofibrillen-Bündeln beteiligt. Eine verminderte Ferroxidase-Aktivität des Amyloid-Vorläuferproteins trägt zu erhöhter zerebraler Eisenakkumulation bei. Die Liquor-Ferritinspiegel bei Trägern des Alzheimer-Risikoallels ApoE4 sind erhöht. Klinisch sind die Eisenspiegel in Basalganglien und Hippocampi negativ mit kognitiven Leistungen assoziiert. Gleichzeitig sind erhöhte Liquor-Ferritinspiegel mit früherem Krankheitsbeginn assoziiert. Schließlich betont die pathologische zerebrale Eisenakkumulation bei allen Subformen der Neurodegeneration mit Eisenablagerung (neurodegeneration with brain iron accumulation, NBIA) die Bedeutung des Eisens für neurodegenerative Erkrankungen.

Abstract

Iron as an essential trace element is a major contributor to many metabolic pathways in the body and the brain. The transfer of iron through the blood-brain barrier and the distribution and storage in the brain is tightly regulated in order to prevent neurotoxicity. Increased iron levels in the ageing brain in cortex and basal ganglia lead to impaired cognitive and motor functions. Moreover, iron contributes to neurodegenerative diseases in the elderly such as Parkinson’s and Alzheimer’s disease. Increased iron deposition in Parkinson’s disease can be found in the substantia nigra where substantial neuronal loss occurs. Iron also promotes aggregation of α-synuclein in Lewy bodies and production of toxic hydroxyl radicals. In Alzheimer’s disease, iron participates in the generation of β-amyloid plaques and neurofibrillary tangles. Vice versa, reduced ferroxidase activity of the amyloid precursor protein contributes to increased cerebral iron accumulation. Ferritin levels in the cerebrospinal fluid (CSF) are increased in patients with the APOE4 allele, a risk factor for Alzheimer’s disease. Clinically, iron levels of the basal ganglia and the hippocampi are negatively associated with cognitive performances. Furthermore, increased CSF ferritin levels are associated with earlier disease onset. Last but not least, the pathological cerebral iron accumulation in the group of disorders called neurodegeneration with brain iron accumulation (NBIA) emphasizes the important role of iron in neurodegenerative diseases.

Schlüsselwörter

Eisen - Altern - Gehirn - Neurodegeneration

Keywords

iron - ageing - brain - neurodegeneration

• Literatur

• 1 Rouault TA. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 2013; 14: 551-564
• 2 Gottschall DW, Dietrich RF, Benkovic SJ et al. Phenylalanine hydroxylase. Correlation of the iron content with activity and the preparation and reconstitution of the apoenzyme. J Biol Chem 1982; 257: 845-849
• 3 Ramsey AJ, Hillas PJ, Fitzpatrick PF. Characterization of the active site iron in tyrosine hydroxylase. Redox states of the iron. J Biol Chem 1996; 271: 24395-24400
• 4 Algarin C, Peirano P, Garrido M et al. Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr Res 2003; 53: 217-223
• 5 Gunshin H, Fujiwara Y, Custodio AO et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005; 115: 1258-1266
• 6 Shayeghi M, Latunde-Dada GO, Oakhill JS et al. Identification of an intestinal heme transporter. Cell 2005; 122: 789-801
• 7 Donovan A, Lima CA, Pinkus JL et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1: 191-200
• 8 Jefferies WA, Brandon MR, Hunt SV et al. Transferrin receptor on endothelium of brain capillaries. Nature 1984; 312: 162-163
• 9 Ward RJ, Zucca FA, Duyn JH et al. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 2014; 13: 1045-1060
• 10 Moos T, Rosengren Nielsen T, Skjorringe T et al. Iron trafficking inside the brain. J Neurochem 2007; 103: 1730-1740
• 11 Dringen R, Bishop GM, Koeppe M et al. The pivotal role of astrocytes in the metabolism of iron in the brain. Neurochem Res 2007; 32: 1884-1890
• 12 Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 2003; 278: 27144-27148
• 13 Moos T, Oates PS, Morgan EH. Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency. J Comp Neurol 1998; 398: 420-430
• 14 Moos T, Morgan EH. The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J Neurochem 2004; 88: 233-245
• 15 Boserup MW, Lichota J, Haile D et al. Heterogenous distribution of ferroportin-containing neurons in mouse brain. Biometals 2011; 24: 357-375
• 16 Todorich B, Zhang X, Slagle-Webb B et al. Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem 2008; 107: 1495-1505
• 17 Schulz K, Vulpe CD, Harris LZ et al. Iron efflux from oligodendrocytes is differentially regulated in gray and white matter. J Neurosci 2011; 31: 13301-13311
• 18 Wu J, Hua Y, Keep RF et al. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 2003; 34: 2964-2969
• 19 Hare D, Ayton S, Bush A et al. A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci 2013; 5: 34
• 20 Stadtman ER, Oliver CN. Metal-catalyzed oxidation of proteins. Physiological consequences. J Biol Chem 1991; 266: 2005-2008
• 21 Cobb CA, Cole MP. Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 2015;
• 22 Zecca L, Stroppolo A, Gatti A et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci U S A 2004; 101: 9843-9848
• 23 Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem 1958; 3: 41-51
• 24 Daugherty A, Raz N. Age-related differences in iron content of subcortical nuclei observed in vivo: a meta-analysis. Neuroimage 2013; 70: 113-121
• 25 Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease – systematic review and meta-analysis. Neurobiol Aging 2009; 30: 337-352
• 26 Penke L, Valdes Hernandez MC, Maniega SM et al. Brain iron deposits are associated with general cognitive ability and cognitive aging. Neurobiol Aging 2012; 33: 510 e512-517 e512
• 27 Cass WA, Grondin R, Andersen AH et al. Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys. Neurobiol Aging 2007; 28: 258-271
• 28 Smith CD, Umberger GH, Manning EL et al. Critical decline in fine motor hand movements in human aging. Neurology 1999; 53: 1458-1461
• 29 Bennett DA, Beckett LA, Murray AM et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 1996; 334: 71-76
• 30 Popescu BF, George MJ, Bergmann U et al. Mapping metals in Parkinson’s and normal brain using rapid-scanning x-ray fluorescence. Phys Med Biol 2009; 54: 651-663
• 31 Castellani RJ, Siedlak SL, Perry G et al. Sequestration of iron by Lewy bodies in Parkinson’s disease. Acta Neuropathol 2000; 100: 111-114
• 32 Kostka M, Hogen T, Danzer KM et al. Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 2008; 283: 10992-11003
• 33 Levin J, Hogen T, Hillmer AS et al. Generation of ferric iron links oxidative stress to alpha-synuclein oligomer formation. J Parkinsons Dis 2011; 1: 205-216
• 34 Logroscino G, Gao X, Chen H et al. Dietary iron intake and risk of Parkinson’s disease. Am J Epidemiol 2008; 168: 1381-1388
• 35 Huls S, Hogen T, Vassallo N et al. AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced alpha-synuclein oligomers. J Neurochem 2011; 117: 868-878
• 36 Turnbull S, Tabner BJ, El-Agnaf OM et al. alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med 2001; 30: 1163-1170
• 37 Martin WR, Wieler M, Gee M. Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 2008; 70: 1411-1417
• 38 Berg D, Seppi K, Behnke S et al. Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons. Arch Neurol 2011; 68: 932-937
• 39 Berg D, Grote C, Rausch WD et al. Iron accumulation in the substantia nigra in rats visualized by ultrasound. Ultrasound Med Biol 1999; 25: 901-904
• 40 Ben-Shachar D, Youdim MB. Intranigral iron injection induces behavioral and biochemical “parkinsonism” in rats. J Neurochem 1991; 57: 2133-2135
• 41 Kaur D, Peng J, Chinta SJ et al. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging 2007; 28: 907-913
• 42 Kaur D, Yantiri F, Rajagopalan S 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
• 43 Salazar J, Mena N, Hunot S et al. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci U S A 2008; 105: 18578-18583
• 44 Ayton S, Lei P, Duce JA et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 2013; 73: 554-559
• 45 Devos D, Moreau C, Devedjian JC et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 2014; 21: 195-210
• 46 Lovell MA, Robertson JD, Teesdale WJ et al. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 1998; 158: 47-52
• 47 Sayre LM, Perry G, Harris PL et al. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem 2000; 74: 270-279
• 48 Rogers JT, Randall JD, Cahill CM et al. An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 2002; 277: 45518-45528
• 49 Yamamoto A, Shin RW, Hasegawa K 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
• 50 Nubling G, Bader B, Levin J et al. Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with alpha-synuclein at the single molecule level. Mol Neurodegener 2012; 7: 35
• 51 Duce JA, Tsatsanis A, Cater MA et al. Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 2010; 142: 857-867
• 52 Khatoon S, Grundke-Iqbal I, Iqbal K. Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett 1994; 351: 80-84
• 53 Lei P, Ayton S, Finkelstein DI et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 2012; 18: 291-295
• 54 Zhu WZ, Zhong WD, Wang W et al. Quantitative MR phase-corrected imaging to investigate increased brain iron deposition of patients with Alzheimer disease. Radiology 2009; 253: 497-504
• 55 Raha AA, Vaishnav RA, Friedland RP et al. The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease. Acta Neuropathol Commun 2013; 1: 55
• 56 Smith MA, Zhu X, Tabaton M et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 2010; 19: 363-372
• 57 Corrigan FM, Reynolds GP, Ward NI. Hippocampal tin, aluminum and zinc in Alzheimer’s disease. Biometals 1993; 6: 149-154
• 58 Crapper McLachlan DR, Dalton AJ, Kruck TP et al. Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 1991; 337: 1304-1308
• 59 Ayton S, Faux NG, Bush AI et al. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun 2015; 6: 6760
• 60 Bester J, Buys AV, Lipinski B et al. High ferritin levels have major effects on the morphology of erythrocytes in Alzheimer’s disease. Front Aging Neurosci 2013; 5: 88
• 61 Hogarth P. Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord 2015; 8: 1-13
• 62 Zhou B, Westaway SK, Levinson B et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001; 28: 345-349
• 63 Hayflick SJ, Westaway SK, Levinson B et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003; 348: 33-40
• 64 Kruer MC. The neuropathology of neurodegeneration with brain iron accumulation. Int Rev Neurobiol 2013; 110: 165-194
• 65 Zorzi G, Zibordi F, Chiapparini L et al. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 2011; 26: 1756-1759
• 66 Morgan NV, Westaway SK, Morton JE et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 2006; 38: 752-754
• 67 Paisan-Ruiz C, Bhatia KP, Li A et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 2009; 65: 19-23
• 68 Yoshino H, Tomiyama H, Tachibana N et al. Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology 2010; 75: 1356-1361
• 69 Illingworth MA, Meyer E, Chong WK et al. PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Mol Genet Metab 2014; 112: 183-189
• 70 Hartig MB, Iuso A, Haack T et al. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet 2011; 89: 543-550
• 71 Hogarth P, Gregory A, Kruer MC et al. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 2013; 80: 268-275
• 72 Haack TB, Hogarth P, Kruer MC et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 2012; 91: 1144-1149
• 73 Hayflick SJ, Kruer MC, Gregory A et al. beta-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 2013; 136: 1708-1717
• 74 Paudel R, Li A, Wiethoff S et al. Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy. Acta Neuropathol Commun 2015; 3: 39
• 75 Kruer MC, Paisan-Ruiz C, Boddaert N et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 2010; 68: 611-618
• 76 Dusi S, Valletta L, Haack TB et al. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet 2014; 94: 11-22
• 77 Curtis AR, Fey C, Morris CM et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 2001; 28: 350-354
• 78 Yoshida K, Furihata K, Takeda S et al. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 1995; 9: 267-272
• 79 Alazami AM, Al-Saif A, Al-Semari A et al. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet 2008; 83: 684-691
• 80 Ramirez A, Heimbach A, Grundemann J et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38: 1184-1191