Oxidative stress and neural dysfunction in Down Syndrome

  • R. C. Iannello
  • P. J. Crack
  • J. B. de Haan
  • I. Kola
Conference paper


Total or partial trisomy of chromosome 21 occurs with relatively high frequency and is responsible for the occurrence of Down syndrome. Phenotypically, individuals with Down syndrome display characteristic morphological features and a variety of clinical disorders. One of the challenges for researchers in this field has been to ascertain and understand the relationship between the Down syndrome phenotype with the gene dosage effect resulting from trisomy of chromosome 21. Much attention therefore, has been given towards investigating the consequences of overexpressing chromosome 21-linked genes. In particular, an extensive analysis of SOD1 and APP have provided important insights as to how perturbations in the expression of their respective genes may contribute to the Down syndrome phenotype. In this review we will highlight studies which support a key role for SOD1 and APP in the pathogenesis of neural abnormalities observed in individuals with Down syndrome. Central to this relationship is how the redox state of the cell is affected and its consequences to neural function and integrity.


Amyotrophic Lateral Sclerosis Down Syndrome Familial Amyotrophic Lateral Sclerosis Partial Trisomy Down Syndrome Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anneren G, Epstein CJ (1987) Lipid peroxidation and superoxide dismutase-1 and glutathione peroxidase activities in trisomy 16 fetal mice and human trisomy 21 fibroblasts. Pediatr Res 21: 88–92PubMedCrossRefGoogle Scholar
  2. Anneren G, Edman B (1993) Down syndrome-a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide-dismutase type 1 (SOD-1) gene. APMIS [Suppl] 40: 71–79Google Scholar
  3. Avraham KB, Schickler M, Sapoznikov D, Yarom R, Groner Y (1988) Down’s syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase. Cell 54(6): 823–829PubMedCrossRefGoogle Scholar
  4. Avraham KB, Sugarman H, Rotshenker S, Groner Y (1991) Down’s syndrome: morphological remodeling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice. J Neurocytol 20(3): 208–215PubMedCrossRefGoogle Scholar
  5. Baker MS, Gebicki JM (1984) The effect of pH on the conversion of superoxide to hydroxyl free radicals. Arch Biochem Biophys 234: 258–262PubMedCrossRefGoogle Scholar
  6. Barkats M, Bertholet JY, Venault P, Ceballos-Picot I, Nicole A, Phillips J, Moutier R, Roubertoux P, Sinet PM, Cohen-Salmon C (1993) Hippocampal mossy fiber changes in mice transgenic for the human copper-zinc superoxide dismutase gene. Neurosci Lett 160(1): 24–28PubMedCrossRefGoogle Scholar
  7. Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77(6): 817–827PubMedCrossRefGoogle Scholar
  8. Bogdanov MB, Ramos LE, Xu Z, Beal MF (1998) Elevated “hydroxyl radical” generation in vivo in an animal model ofamyotrophic lateral sclerosis. J Neurochem 71(3): 1321–1324PubMedCrossRefGoogle Scholar
  9. Brodsky G, Otterson GA, Parry BB, Hart I, Patterson D, Kaye FJ (1995) Localization of STCH to human chromosome 21q11.1. Genomics 30(3): 627–628PubMedCrossRefGoogle Scholar
  10. Brooksbank BWL, Balazs R (1984) Superoxide dismutase, glutathione peroxidase and lipid peroxidation in Down’s syndrome fetal brain. Dev Brain Res 16: 37–44CrossRefGoogle Scholar
  11. Bruijn LI, Beal MF, Becher MW, Schulz JB, Wong PC, Price DL, Cleveland DW (1997) Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. PNAS 94(14): 7606–7611PubMedCrossRefGoogle Scholar
  12. Busciglio J, Yankner BA (1995) Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378(6559): 776–779PubMedCrossRefGoogle Scholar
  13. Cardasis CA (1983) Ultrastructural evidence of continued reorganization at the aging (11–26 months) rat soleus neuromuscular junction. Anat Rec 207: 399–415PubMedCrossRefGoogle Scholar
  14. Cassarino DS, Bennett JP Jr (1999) An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 29(1): 1–25PubMedCrossRefGoogle Scholar
  15. Caviedes P, Ault B, Rapoport SI (1990) The role of altered sodium currents in action potential abnormalities of cultured dorsal root ganglion neurons from trisomy 21 (Down syndrome) human fetuses. Brain Res 510(2): 229–236PubMedCrossRefGoogle Scholar
  16. Caviedes P, Koistinaho J, Ault B, Rapoport SI (1991) Effects of nerve growth factor on electrical membrane properties of cultured dorsal root ganglia neurons from normal and trisomy 21 human fetuses. Brain Res 556(2): 285–291PubMedCrossRefGoogle Scholar
  17. Ceballos-Picot I, Nicole A, Clement M, Bourre JM, Sinet PM (1992) Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper-zinc superoxide dismutase. Mutat Res 275(3–6): 281–293PubMedGoogle Scholar
  18. Cristiano F, de Haan JB, Iannello RC, Kola I (1995) Changes in the levels of enzymes which modulate the antioxidant balance occur during aging and correlate with cellular damage. Mech Ageing Dev 80(2): 93–105PubMedCrossRefGoogle Scholar
  19. Colon EJ (1972) The structure of the cerebral cortex in Down’s syndrome: a quantitative analysis. Neuropadiatrie 3: 362–376CrossRefGoogle Scholar
  20. Coyle JT, Oster-Granite ML, Gearhart JD (1986) The neurobiologic consequences of Down syndrome. Brain Res Bull 16(6): 773–787PubMedCrossRefGoogle Scholar
  21. Crome L, Stern J (1972) Pathology of mental retardation. In: Crome L, Stern J (eds) Down syndrome. Churchill Livingstone, Edinburgh, pp 200–224Google Scholar
  22. de Haan JB, Newman JD, Kola I (1992) Cu/Zn superoxide dismutase mRNA and enzyme activity, and susceptibility to lipid peroxidation, increases with aging in murine brains. Brain Res Mol Brain Res 13(3): 179–187PubMedCrossRefGoogle Scholar
  23. de Haan JB, Cristiano F, Iannello RC, Kola I (1995) Cu/Zn-superoxide dismutase and glutathione peroxidase during aging. Biochem Mol Biol Int 35(6): 1281–1297PubMedGoogle Scholar
  24. de Haan JB, Cristiano F, Iannello R, Bladier C, Keiner MJ, Kola I (1996) Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum Mol Genet 5(2): 283–292PubMedCrossRefGoogle Scholar
  25. de Haan JB, Wolvetang EJ, Cristiano F, Iannello R, Bladier C, Keiner MJ, Kola I (1997) Reactive oxygen species and their contribution to pathology in Down syndrome. Adv Pharmacol 38: 379–402PubMedCrossRefGoogle Scholar
  26. Epstein CJ (1986) The consequences of chromosome imbalance: principles, mechanisms and models. Cambridge University Press, New YorkCrossRefGoogle Scholar
  27. Fahim MA, Robbins N (1982) Ultrastructural studies of young and old mouse neuromuscular junctions. J Neurocytol 11(4): 641–656PubMedCrossRefGoogle Scholar
  28. Feaster WW, Kwok LW, Epstein CJ (1977) Dosage effects for superoxide dismutase-1 on nucleated cells aneuploid for chromosome 21. Am J Hum Genet 29: 563–570PubMedGoogle Scholar
  29. Fridovich I (1986) Superoxide dismutases. Adv Enzymol Rel Areas Mol Biol 58: 61–97Google Scholar
  30. Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivili X (1995) A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet 4(10): 1935–1944PubMedCrossRefGoogle Scholar
  31. Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269(18): 13623–13628PubMedGoogle Scholar
  32. Gahtan E, Auerbach JM, Groner Y, Segal M (1998) Reversible impairment of long-term potentiation in transgenic Cu/Zn-SOD mice. Eur J Neurosci 10(2): 538–544PubMedCrossRefGoogle Scholar
  33. Galaburda AM, Kemper TL (1979) Cytoarchitectonic abnormalities in developmental dyslexia: a case study. Ann Neurol 6(2): 94–100PubMedCrossRefGoogle Scholar
  34. Groner Y (1995) Transgenic models for chromosome 21 gene dosage effects. Prog Clin Biol Res 393: 193–212PubMedGoogle Scholar
  35. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264(5166): 1772–1775PubMedCrossRefGoogle Scholar
  36. Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. TINS 20: 154–159PubMedGoogle Scholar
  37. Harman D (1994) Free-radical theory of aging: increasing the functional life span. Ann NY Acad Sci 717: 1–15PubMedCrossRefGoogle Scholar
  38. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, Butterfield DA (1994) A model for Beta-amyloid aggregation and neurotoxicity based on free radical generation by the Peptide — relevance to alzheimer disease. PNAS 91(8): 3270–3274PubMedCrossRefGoogle Scholar
  39. Kappas H (1985) Lipid peroxidation: mechanism, analysis, enzymology and biological relevance. In: Sies H (ed) Oxidative stress. Academic Press, London, pp 273–311Google Scholar
  40. Kehrer JP (1993) Free radicals, mediators of tissue injury and disease. Crit Rev Toxicol 23: 21–48PubMedCrossRefGoogle Scholar
  41. Keiner MJ, Estes L, Rutherford M, Uglik SF, Peitzke JA (1997) Heterologous expression of carbonyl reductase: demonstration of prostaglandin 9-ketoreductase activity and paraquat resistance. Life Sci 61: 2317–2322CrossRefGoogle Scholar
  42. Kesslak JP, Nagata SF, Lott I, Nalcioglu O (1994) Magnetic resonance imaging analysis of age-related changes in the brains of individuals with Down’s syndrome. Neurology 44(6): 1039–1045PubMedCrossRefGoogle Scholar
  43. Khan AU, Wilson T (1995) Reactive oxygen species as cellular messengers. Chem Biol 2: 437–445PubMedCrossRefGoogle Scholar
  44. Koizumi S, Ishiguro M, Ohsawa I, Morimoto T, Takamura C, Inoue K, Kohsaka S (1998) The effect of a secreted form of beta-amyloid-precursor protein on intracellular Ca2+ increase in rat cultured hippocampal neurons. Br J Pharmacol 123(8): 1483–1489PubMedCrossRefGoogle Scholar
  45. Kola I (1997) Simple minded mice from “in vivo” libraries. Nature Genet 16: 8–9PubMedCrossRefGoogle Scholar
  46. Kola I, Hertzog PJ (1997) Animal models in the study of the biological function of genes on human chromosome 21 and their role in the pathophysiology of Down syndrome. Hum Mol Genet 6: 1713–1727PubMedCrossRefGoogle Scholar
  47. Korenberg JP (1995) Mental modeling. Nature Genet 11: 109–111PubMedCrossRefGoogle Scholar
  48. Kraus JP, Oliveriusova J, Sokolova J, Kraus E, Vlciek C, de Franchis R, Maclean KN, Bao L, Bukovska G, Patterson D, Pacies V, Ansorge W, Koziich V (1998) The human cystathionine β-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms. Genomics 52: 313–324CrossRefGoogle Scholar
  49. Lejeune J, Gauthier M, Turpin R (1959) Etude des chromosomes somatiques de neufs enfants mongoliens. CR Acad Sci (Paris) 248: 1721–1722Google Scholar
  50. Lyras L, Perry RH, Perry EK, Ince PG, Jenner A, Jenner P, Halliwell B (1998) Oxidative damage to proteins, lipids, and DNA in cortical brain regions from patients with dementia with Lewy bodies. J Neurochem 71(1): 302–312PubMedCrossRefGoogle Scholar
  51. Marin-Padilla M (1972) Pyramidal cell abnormalities in the motor cortex of a child with Down’s aberrations: a Golgi study. Brain Res 44(2): 625–629PubMedCrossRefGoogle Scholar
  52. Marin-Padilla M (1972) Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi study. Brain Res 44(2): 625–629PubMedCrossRefGoogle Scholar
  53. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12(2): 376–389PubMedGoogle Scholar
  54. Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10(2): 243–254PubMedCrossRefGoogle Scholar
  55. Matsuo M (1993) Age-related alterations in antioxidative defense. In: Yu BP (ed) Free radicals in aging. CRC Press, Boca Raton, pp 143–181Google Scholar
  56. Multhaup G, Ruppert T, Schlicksupp A, Hesse L, Beher D, Masters CL, Beyreuther K (1997) Reactive oxygen species and Alzheimer’s disease. Biochem Pharmacol 54(5): 533–559PubMedCrossRefGoogle Scholar
  57. Pappolla MA, Chyan YJ, Omar RA, Hsiao K, Perry G, Smith MA, Bozner P (1998) Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol 152(4): 871–877PubMedGoogle Scholar
  58. Patterson DH (1987) The cause of Down Syndrome. Sci Am 257: 42–49CrossRefGoogle Scholar
  59. Pueschel S (1990) Clinical aspects of Down’s syndrome from infancy to adulthood. Am J Med Genet 7: 52–56Google Scholar
  60. Ross MH, Galaburda AM, Kemper TL (1984) Down’s syndrome: is there a decreased population of neurons? Neurology 34(7): 909–916PubMedCrossRefGoogle Scholar
  61. Rothstein JD, Dykes-Hoberg M, Pardo Ca, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3): 675–686PubMedCrossRefGoogle Scholar
  62. Schuchmann S, Muller W, Heinemann U (1998) Altered Ca2+ signaling and mitochondrial deficiencies in hippocampal neurons of trisomy 16 mice: a model of Down’s syndrome. J Neurosci 18(18): 7216–7231PubMedGoogle Scholar
  63. Scott BS, Petit TL, Becker LE, Edwards BA (1981) Abnormal electric membrane properties of Down’s syndrome DRG neurons in cell culture. Brain Res 254(2): 257–270PubMedGoogle Scholar
  64. Silei V, Fabrizi C, Venturini G, Salmona M, Bugiani O, Tagliavini F, Lauro GM (1999) Activation of microglial cells by PrP and beta-amyloid framenhts raises intracellular calcium through L-type voltage sensitive calcium channels. Brain Res 818(1): 168–170PubMedCrossRefGoogle Scholar
  65. Sinet PM, Michelson AM, Bazin A, Lejeune J, Jerome H (1975) Increase in glutathione peroxidase activity in erythrocytes from trisomy 21 subjects. Biochem Biophys Res Comm 67: 910–915PubMedCrossRefGoogle Scholar
  66. Sumarsono SH, Wilson TJ, Tymms MJ, Venter DJ, Corrick CM, Kola R, Lahoud MH, Papas TS, Seth A, Kola I (1996) Down’s syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 379(6565): 534–537PubMedCrossRefGoogle Scholar
  67. Tanzi RE, Kovacs DM, Kim TW, Moir RD, Guenette SY, Wasco W (1996) The gene defects responsible for familial Alzheimer’s disease. Neurobiol Dis 3(3): 159–168PubMedCrossRefGoogle Scholar
  68. Trotti D, Rolfs A, Danbolt NC, Brown RH, Hediger MA (1999) SOD1 mutants linked to amyotrophic lateral sclerosis inactivate a glial glutamate transporter. Nat Neurosci 2(5): 427–433PubMedCrossRefGoogle Scholar
  69. van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Koycu S, Ramdjielal RDJ, Salehi A, Martens GJM, Grosveld FG, Peter J, Burbach H, Hol EM (1998) Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer’s and Down patients. Science 279(5348): 242–247PubMedCrossRefGoogle Scholar
  70. Wermeth B (1982) Enzymology of carbonyl metabolism. AR Liss, New York, pp 261–274Google Scholar
  71. Winyard PG, Blake DR (1997) Antioxidants, redox-regulated transcription factors, and inflammation. Adv Pharmacol 38: 403–421PubMedCrossRefGoogle Scholar
  72. Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, et al (1995) Non-enzymatically glycated tau in Alzheimer’s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med 1(7): 693–699PubMedCrossRefGoogle Scholar
  73. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382(6593): 685–691PubMedCrossRefGoogle Scholar
  74. Yarom R, Sagher U, Havivi Y, Peled IJ, Wexler MR (1986) Myofibers in tongues of Down’s syndrome. J Neurol Sci 73(3): 279–287PubMedCrossRefGoogle Scholar
  75. Yarom R, Sherman Y, Sagher U, Peled IJ, Wexler MR, Gorodetsky R, (1987) Elevated concentrations of elements and abnormalities of neuromuscular junctions in tongue muscles of Down’s syndrome. J Neurol Sci 79(3): 315–326PubMedCrossRefGoogle Scholar
  76. Yarom R, Sapoznikov D, Havivi Y, Avraham KB, Schickler M, Groner Y (1988) Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down’s syndrome. J Neurol Sci 88(1–3): 41–53PubMedCrossRefGoogle Scholar
  77. Yim MB, Chock PB, Stadtman ER (1993) Enzyme function of copper, zinc superoxide as a free radical generator. J Biol Chem 268: 4099–4105PubMedGoogle Scholar
  78. Yu BP (1994) Cellular defenses against damage from reactive oxygen species. Physiol Rev 74: 139–162PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • R. C. Iannello
    • 1
  • P. J. Crack
    • 1
  • J. B. de Haan
    • 1
  • I. Kola
    • 1
  1. 1.Centre for Functional Genomics and Human Disease, Institute of Reproduction and DevelopmentMonash Medical CentreClaytonAustralia

Personalised recommendations