Apoptosis

, Volume 18, Issue 2, pp 121–134 | Cite as

Apoptosis in Down’s syndrome: lessons from studies of human and mouse models

  • Noemí Rueda
  • Jesús Flórez
  • Carmen Martínez-Cué
Original Paper

Abstract

Down syndrome (DS) is the most common chromosomal abnormality in humans. DS is characterized by a number of phenotypes, including the development of Alzheimer’s disease-like pathology and immunological, hematological and cardiovascular alterations. Apoptosis or programmed cell death is physiologically involved in development and aging, as well as in numerous pathological processes. Altered apoptosis has been proposed as a putative mechanism underlying many DS phenotypes. Evidence from human and animal studies indicates that apoptosis does not have a prominent role in the disturbances found in brain development in trisomy 21. However, alterations in apoptosis have been associated with neurodegeneration in the aging DS brain, with impairments in general growth and with immunological, cardiovascular and oncological alterations. Altered apoptosis in DS is likely to be the result of the interplay between several chromosome 21 (Hsa21) and non-Hsa21 genes. The interplay between these genes may affect physiological programmed cell death either directly, by modifying the activity of the apoptotic pathways, or indirectly, by inducing degeneration and rendering the cell more vulnerable to apoptosis-inducing factors.

Keywords

Down syndrome Apoptosis Mouse models of Down syndrome 

References

  1. 1.
    Shin M, Besser LM, Kucik JE, Lu C, Siffel C, Correa A (2009) Prevalence of Down syndrome among childrent and adolescent in 10 regions of the United States. Pediatrics 124:1565–1571PubMedCrossRefGoogle Scholar
  2. 2.
    Nadel L (2003) Down’s syndrome: a genetic disorder in biobehavioral perspective. Genes Brain Behav 2:156–166PubMedCrossRefGoogle Scholar
  3. 3.
    Vicari S (2004) Memory development and intellectual disabilities. Acta Pediatr 93:60–64CrossRefGoogle Scholar
  4. 4.
    Cenini G, Dowling AL, Beckett TL, Barone E, Mancuso C, Murphy MP, Levine H, Lott IT, Schmitt FA, Butterfield DA, Head E (2012) Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome. Biochem Biophys Acta 1822:130–138PubMedCrossRefGoogle Scholar
  5. 5.
    Sabbagh MN, Fleisher A, Chen K, Rogers J, Berk C, Reiman E, Pontecorvo M, Mintun M, Skovronsky D, Jacobson SA, Sue LI, Liebsack C, Charney AS, Cole L, Belden C, Beach TG (2011) Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with Down syndrome and Alzheimer disease. Arch Neurol 68:1461–1466PubMedCrossRefGoogle Scholar
  6. 6.
    Levin S, Schesinger M, Handzel Z, Hahn T, Altman Y, Czernobilsky B, Boss J (1979) Thymic deficiency in Down’s syndrome. Pediatrics 63:80–87PubMedGoogle Scholar
  7. 7.
    Roizen NJ, Amarose AP (1993) Hematologic abnormalities in children with Down syndrome. Am J Med Genet 46:510–512PubMedCrossRefGoogle Scholar
  8. 8.
    McElhinney DB, Straka M, Goldmuntz E, Zackai EH (2002) Correlation between abnormal cardiac physical examination and echocardiographic findings in neonates with Down syndrome. Am J Med Genet 113:238–241PubMedCrossRefGoogle Scholar
  9. 9.
    Roizen NJ, Patterson D (2003) Down’s syndrome. Lancet 361:1281–1289PubMedCrossRefGoogle Scholar
  10. 10.
    Gurbuxani S, Vyas P, Crispino JD (2004) Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103:399–406PubMedCrossRefGoogle Scholar
  11. 11.
    Bartesaghi R, Guidi S, Ciani E (2011) Is it possible to improve neurodevelopmental abnormalities in Down syndrome? Rev Neurosci 22:419–455PubMedGoogle Scholar
  12. 12.
    Rueda N, Flórez J, Martínez-Cué C (2012) Mouse models of Down syndrome as a tool to unravel the causes of mental disabilities. Neural Plast 2012:584071PubMedCrossRefGoogle Scholar
  13. 13.
    Gropp A, Kolbus U, Giers D (1975) Systematic approach to the study of trisomy in the mouse. II. Cytogenet Cell Genet 14:42–62PubMedCrossRefGoogle Scholar
  14. 14.
    Sturgeon X, Gardiner KJ (2011) Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions. Mamm Genome 22:261–271PubMedCrossRefGoogle Scholar
  15. 15.
    Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, Epstein CJ, Huang TT (1998) Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA 95(11):6256–6261PubMedCrossRefGoogle Scholar
  16. 16.
    Roper RJ, St John HK, Philip J, Lawler A, Reeves RH (2006) Perinatal loss of Ts65Dn Down syndrome mice. Genetics 172:437–443PubMedCrossRefGoogle Scholar
  17. 17.
    Cefalu JA, Croom WJJ, Eisen EJ, Jones EE, Daniel LR, Taylor IL (1998) Jejunal function and plasma amino acid concentrations in the segmental trisomic Ts65Dn mouse. Growth Dev Aging 62:47–59PubMedGoogle Scholar
  18. 18.
    Paz-Miguel JE, Flores R, Sánchez-Velasco P, Ocejo-Vimyals G, Escribano de Diego J, López de Rego J, Leyva-Cobián F (1999) Reactive oxygen intermediates during programmed cell death induced in the thymus of the Ts65Dn mouse, a murine model for human Down’s syndrome. J Immunol 163:5399–5410PubMedGoogle Scholar
  19. 19.
    Kirsammer G, Jilani S, Liu H, Davis E, gurbuxani S, Le Beau MM, Crispino JD (2008) Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 111:767–775PubMedCrossRefGoogle Scholar
  20. 20.
    Richtsmeier JT, Zumwalt A, Carlson EJ, Epstein CJ, Reeves RH (2002) Craniofacial phenotypes in segmentally trisomic mouse models for Down syndrome. Am J Med Genet 107:317–324PubMedCrossRefGoogle Scholar
  21. 21.
    Hill CA, Reeves RH, Richtsmeier JT (2007) Effects of aneuplidy on skull growth in a mouse model of Down syndrome. J Anat 210:394–405PubMedCrossRefGoogle Scholar
  22. 22.
    Moore CS (2006) Postnatal lethality and cadiac anomalies in the Ts65Dn Down syndrome mouse model. Mamm Genome 17:1005–1012PubMedCrossRefGoogle Scholar
  23. 23.
    O’Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, Sesay A, Modino S, Vanes L, Hernandez D, Linehan JM, Sharpe PT, Brandner S, Bliss TV, Henderson DJ, Nizetic D, Tybulewicz VL, FFisher EM (2005) An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309:2033–2037PubMedCrossRefGoogle Scholar
  24. 24.
    Yu T, Li Z, Jia Z, Clapcote SJ, Li S, Asrar S, Pao A, Chen R, Fan N, Carattini-Rivera S, Bechard AR, Spring S, Henkelman RM, Stoica G, Matsui S, Nowak NJ, Roder JC, Chen C, Bradley A, Yu YE (2010) A mouse model of Down syndrome trisomic for all human chromosome 21 syntnic regions. Hum Mol Genet 19:2780–2791PubMedCrossRefGoogle Scholar
  25. 25.
    Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14:453–501PubMedCrossRefGoogle Scholar
  26. 26.
    Caviness VS, Takahashi T, Nowakowski RS (1995) Numbers, time and neocortical neuronogenesis: a general developmental and evolutionary model. Trends Neurosci 18:379–383PubMedCrossRefGoogle Scholar
  27. 27.
    Blaschke AJ, Staley K, Chun J (1996) Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex. Development 122:1165–1174PubMedGoogle Scholar
  28. 28.
    Haydar TF, Kuan C-Y, Flavel RA, Rakic P (1999) The role of cell death in regulating the size and shape of the mammalian forebrain. Cereb Cortex 9:621–626PubMedCrossRefGoogle Scholar
  29. 29.
    Jovanović Z (2012) Mechanisms of neurodegeneration in Alzheimer’s disease. Med Pregl 65:301–307PubMedCrossRefGoogle Scholar
  30. 30.
    Verri M, Pastoris O, Dossena M, Aquilani R, Guerriero F, Cuzzoni G, Venturini L, Ricevuti G, Bongiorno AI (2012) Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer’s disease. Int J Immunopathol Pharmacol 25:345–353PubMedGoogle Scholar
  31. 31.
    Perier C, Bové J, Vila M (2012) Mitochondria and programmed cell death in Parkinson’s disease: apoptosis and beyond. Antioxid Redox Signal 16:883–895PubMedCrossRefGoogle Scholar
  32. 32.
    Murase S, Owens DF, McKay RD (2011) In the newborn hippocampus, neurotrophin-dependent survival requires spontaneous activity and integrin signaling. J Neurosci 31:7791–7800PubMedCrossRefGoogle Scholar
  33. 33.
    Barde YA (1994) Neurotrophins: a family of proteins supporting the survival of neurons. Prog Clin Biol Res 390:45–56PubMedGoogle Scholar
  34. 34.
    Zimmermann KC, Bonzon C, Green DR (2001) The machinery of programmed cell death. Pharmacol Ther 92:57–70PubMedCrossRefGoogle Scholar
  35. 35.
    Budihardjo I, Oliver H, Lutter M, Luo X, Wang W (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290PubMedCrossRefGoogle Scholar
  36. 36.
    Jiang X, Wang X (2004) Cytochrome C-mediated apoptosis. Annu Rev Biochem 73:87–106PubMedCrossRefGoogle Scholar
  37. 37.
    Hockenbery DM, Oltvai ZM, Yin XM, Milliman CL, Korsmeyer SJ (1993) Bcl-2 funtions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251PubMedCrossRefGoogle Scholar
  38. 38.
    Kroemer G (1997) The proto-oncogene Bcl-2 and its rele in regulating apoptosis. Nat Med 3:614–620PubMedCrossRefGoogle Scholar
  39. 39.
    Cory S, Adams JM (2002) The Bcl-2 family: regulators of the cellular life-or-death swich. Nat Rev Cancer 2:647–656PubMedCrossRefGoogle Scholar
  40. 40.
    Yang E, Zha J, Jockel J, Boise LH, Thomson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-xl and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291PubMedCrossRefGoogle Scholar
  41. 41.
    Wisniewski KE (1990) Down syndrome children often have brain with maturation delay, retardation of growth and cortical dysgenesis. Am J Med Genet 7:274–281Google Scholar
  42. 42.
    Golden JA, Hyman BT (1994) Development of the superior temporal neuocortex is anomalous in trisomy 21. J Neuropathol Exp Neurol 53:513–520PubMedCrossRefGoogle Scholar
  43. 43.
    Guidi S, Bonasoni P, Ceccarelli C, Santini D, Gualtieri F, Ciani E, Bartesaghi R (2008) Neurogenesis impairment and increased cell death reduce total neuron number in the hippocampal region of foetuses with Down syndrome. Brain Pathol 18:180–197PubMedCrossRefGoogle Scholar
  44. 44.
    Guidi S, Ciani E, Bonasoni P, Santini D, Bartesaghi R (2010) Widespread proliferation impairment and hypocellularity in the cerebellum of fetuses with Down syndrome. Brain Pathol 21:361–373PubMedCrossRefGoogle Scholar
  45. 45.
    Larsen KB, Laursen H, Graemb N, Samuelsena GB, Bogdanovicc N, Pakkenberga B (2008) Reduced cell number in the neocortical part of the human fetal brain in Down syndrome. Ann Anat 190:421–427PubMedCrossRefGoogle Scholar
  46. 46.
    Chakrabarti L, Galdzicki Z, Haydar TF (2007) Defects in embryonic neurogenesis and initial synapse formation in the forebrain of the Ts65Dn mouse model of Down syndrome. J Neurosci 27:11483–11495PubMedCrossRefGoogle Scholar
  47. 47.
    Insausti AM, Megías M, Crespo D, Cruz-Orive LM, Dierssen M, Vallina IF, Insausti R, Flórez J (1998) Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of Down syndrome. Neurosci Lett 253:1–4CrossRefGoogle Scholar
  48. 48.
    Kurt MA, Kafa MI, Dierssen M, Davies DC (2004) Deficits in neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome. Brain Res 1022:101–109PubMedCrossRefGoogle Scholar
  49. 49.
    Lorenzi HA, Reeves RH (2006) Hipocampal hipocellularity in the Ts65Dn mouse originates early in development. Brain Res 1104:153–159PubMedCrossRefGoogle Scholar
  50. 50.
    Contestabile A, Fila T, Ceccarelli C, Bonasoni P, Bonapace L, Santini D, Bartesaghi R, Ciani E (2007) Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with Down síndrome and in Ts65Dn mice. Hippocampus 17:665–678PubMedCrossRefGoogle Scholar
  51. 51.
    Llorens-Martín MV, Rueda N, Tejeda GS, Flórez J, Trejo JL, Martínez-Cué C (2010) Effects of voluntary physical exercise on adult hippocampal neurogenesis and behavior of Ts65Dn mice, a model of Down syndrome. Neuroscience 171:1228–1240PubMedCrossRefGoogle Scholar
  52. 52.
    Rueda N, Llorens-Martin M, Florez J, Valdizan E, Banerjee P, Trejo JL, Martínez-Cué C (2010) Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J Alzheimers Dis 21:277–290PubMedGoogle Scholar
  53. 53.
    Baxter LL, Moran TH, Richtsmeier JT, Troncoso J, Reeves RH (2000) Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum Mol Genet 9:105–202CrossRefGoogle Scholar
  54. 54.
    Roper RJ, Baxter LL, Saran NG, Klinedinst DK, Beachy PA, Reeves RH (2006) Defective cerebellar esponse to mitogenic Hedgehog signaling in Down syndrome mice. Proc Natl Acad Sci USA 103:1452–1456PubMedCrossRefGoogle Scholar
  55. 55.
    Contestabile A, Fila T, Bartesaghi R, Ciani E (2009) Cell cycle elongation impairs proliferation of cerebellar granule cell precursors in the Ts65Dn mouse, an animal model for Down syndrome. Brain Pathol 19:224–237PubMedCrossRefGoogle Scholar
  56. 56.
    Olson LE, Roper RJ, Baxtr LL, Carlson EJ, Epstein CJ, Reeves RH (2004) Down syndrome mouse models Ts65Dn, Ts1Cje and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev Dyn 230:581–589PubMedCrossRefGoogle Scholar
  57. 57.
    Busciglio J, Yankner BA (1995) Apoptosis and increased generation of reactive oxygen species in Down′s syndrome neurons in vitro. Nature 378:776–779PubMedCrossRefGoogle Scholar
  58. 58.
    Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H, Yankner BA (2002) Altered metabolism of the amyloid β precursor protein is associated with Mitochondrial dysfunction in Down′s syndrome. Neuron 33:677–688PubMedCrossRefGoogle Scholar
  59. 59.
    Pelsman A, Hoyo-Vadillo C, Gudasheva TA, Seredenin SB, Ostrovskaya RU, Busciglio J (2003) GVS-111 prevents oxidative damage and apoptosis in normal and Down’s syndrome human cortical neurons. Int J Dev Neurosci 21:117–124PubMedCrossRefGoogle Scholar
  60. 60.
    Helguera P, Pelsman A, Pigino G, Wolvetang E, Head E, Busciglio J (2005) Ets-2 pronotes the activation of a mitocondrial death pathway in Down′s syndrome neurons. J Neurosci 25:2295–2303PubMedCrossRefGoogle Scholar
  61. 61.
    Seild R, Bidmon B, Bajo M, Yoo PC, Cairns N, LaCasse EC, Lubec G (2001) Evidence for apoptosis in the fetal Down syndrome brain. J Child Neurol 16:438–442Google Scholar
  62. 62.
    Abraham H, Tornoczky T, Kosztolanyi G, Seress L (2001) Cell formation in the cortical layers of the developing human cerebelloun. Int J Dev Neurosci 19:53–62PubMedCrossRefGoogle Scholar
  63. 63.
    Gulesserian T, Engidawork E, Yoo BC, Cairns N, Lubec G (2001) Alteration of caspases and other apoptosis regulatory proteins in Down syndrome. J Neural Transm Suppl 61:163–179PubMedGoogle Scholar
  64. 64.
    Engidawork E, Balic N, Juranville JF, Fountoulakis M, Dierssen M, Lubec G (2001) Unaltered expression of Fas (CD95/APO-1), Caspase-3, Bcl-2 and annexins in brains of fetal Down syndrome: evidence against increased apoptosis. J Neural Transm Suppl 61:149–162PubMedGoogle Scholar
  65. 65.
    Bhattacharyya A, McMillan E, Chen SI, Wallace K, Svendsen CN (2009) A critical period in cortical interneuron neurogenesis in Down syndrome revealed by human neural progenitor cells. Dev Neurosci 31:497–510PubMedCrossRefGoogle Scholar
  66. 66.
    Kadota M, Shirayoshi Y, Oshimura M (2002) Elevated apoptosis in pre-mature neurons differentiated from mouse ES cells containing a single human chromosome 21. Biochem Biophys Res Commun 299:599–605PubMedCrossRefGoogle Scholar
  67. 67.
    Bambrick LL, Krueger BK (1999) Neuronal apoptosis in mouse trysomy 16: mediation by caspases. J Neurochem 72:1769–1772PubMedCrossRefGoogle Scholar
  68. 68.
    Stabel-Burow J, Kleu A, Schuchmann S, Heinemann U (1997) Glutathione levels and nerve cell loss in hippocampal cultures from trisomy 16 mouse—a model of Down syndrome. Brain Res 765:313–318PubMedCrossRefGoogle Scholar
  69. 69.
    Schumann S, Heinemann U (2000) Diminished glutathione levels cause spontaneous mitochondria-mediated cell death in neurons from trisomy 16 mice: a model of Down’s syndrome. J Neurochem 74:1205–1214CrossRefGoogle Scholar
  70. 70.
    Haydar TF, Nowakowski RS, Yarowsky PJ, Krueger BK (2000) Role of founder cell deficit and delayed neuronogeneis in microencephaly of the trisomy 16 mouse. J Neurosci 20:4156–4164PubMedGoogle Scholar
  71. 71.
    Spreafico R, Frassoni C, Arclli P, Selvaggio M, De Biasi S (1995) In situ labeling of apoptotic cell death in the cerebral córtex and thalamus of rats during development. J Comp Neurol 363:281–295PubMedCrossRefGoogle Scholar
  72. 72.
    Thomaidou D, Mioni MC, Cavanagh JFR, Parnavelas JG (1997) Apoptosis and its relation to the cell cycle in the developing cerebral córtex. J Neurosci 17:1075–1085PubMedGoogle Scholar
  73. 73.
    Kim WR, Sun W (2011) Programmed cell death during postnatal development of the rodent nervous system. Dev Growth Differ 53:225–235PubMedCrossRefGoogle Scholar
  74. 74.
    Kesslak JP, Nagata SF, Lott I, Nalciouglu O (1994) Magnetic resonance imaging analysis of age-related changes in the brains of individuals with Down’s syndrome. Neurology 44:1039–1045PubMedCrossRefGoogle Scholar
  75. 75.
    Krasuski JS, Alexander GE, Horwitz B, Rapoport SI, Schapiro MB (2002) Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down’s syndrome: implications for the prodromal phase of Alzheimer’s disease. Am J Psychiatry 159:74–81PubMedCrossRefGoogle Scholar
  76. 76.
    Teipel SJ, Alexander GE, Schapiro MB, Möller HJ, Rapoport SI, Hampel H (2004) Age-related cortical grey matter reductions in non-demented Down’s syndrome adults determined by MRI with voxel-based morphometry. Brain 127:811–824PubMedCrossRefGoogle Scholar
  77. 77.
    Teipel SJ, Hampel H (2006) Neuroanatomy of Down syndrome in vivo: a model of preclinical Alzheimer’s disease. Behav Genet 36:405–415PubMedCrossRefGoogle Scholar
  78. 78.
    Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Arao C (1989) Brain interleukin I and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86:7611–7615PubMedCrossRefGoogle Scholar
  79. 79.
    Wenk GL, McGann K, Mencarelli A, Hauss-Wegrzyniak B, Del Doldato P, Fiorucci S (2000) Mechanisms to prevent the toxicity of chronic neuroinflammtion on forebrain cholinergic neurons. Eur J Pharmacol 402:77–85PubMedCrossRefGoogle Scholar
  80. 80.
    Jovanovic SV, Clements D, MacLeod K (1998) Biomarkers of oxidative stress are significantly elevated in Down syndrome. Free Radic Biol Med 25:1044–1048PubMedCrossRefGoogle Scholar
  81. 81.
    Capone G, Kim P, Jovanovich S, Payne L, Freund L, Welch K, Miller E, Trush M (2002) Evidence for increased mitochondrial superoxide production in Down syndrome. Life Sci 70:2885–2895PubMedCrossRefGoogle Scholar
  82. 82.
    Granholm AC, Sanders LA, Crnic LS (2000) Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down’s syndrome. Exp Neurol 161:647–663PubMedCrossRefGoogle Scholar
  83. 83.
    Hunter CL, Bachman D, Granholm AC (2004) Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome. Ann Neurol 56:675–688PubMedCrossRefGoogle Scholar
  84. 84.
    Contestabile A, Ciani E, Contestabile A (2008) The place of choline acetyltransferase activity measurement in the “cholinergic hypothesis” of neurodegenerative diseases. Neurochem Res 33:318–327PubMedCrossRefGoogle Scholar
  85. 85.
    Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm AC (2009) Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrom mouse model. Exp Neurol 216:278–289PubMedCrossRefGoogle Scholar
  86. 86.
    Shichiri M, Yoshida Y, Ishida N, Hagihara Y, Iwahashi H, Tamai H, Niki E (2011) alpha-Tocopherol suppreses lipid peroxiation and behavioural and cognitive impairments in the Ts65Dn mouse model of Down syndrome. Free Radic Biol Med 15:1801–1811CrossRefGoogle Scholar
  87. 87.
    Johnson EM (1994) Possible role of neuronal apoptosis in Alzheimer’s disease. Neurobiol Aging 2:S187–S189CrossRefGoogle Scholar
  88. 88.
    Wellington CL, Hayden MR (2000) Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin Genet 57:1–510PubMedCrossRefGoogle Scholar
  89. 89.
    Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Brück W, Jellinger K, Lassmann H (1999) Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. Am J Pathol 155:1459–1466PubMedCrossRefGoogle Scholar
  90. 90.
    Anderson AJ, Stoltzner S, Lai F, Su J, Nixon RA (2000) Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, an effect of post-mortem tissue archival on TUNEL. Neurobiol Aging 21:511–524PubMedCrossRefGoogle Scholar
  91. 91.
    De la Monte SM (1999) Molecular abnormalities of the brain in Down syndrome: relevance to Alzheimer’s neurodegeneration. J Neural Transm Suppl 57:1–19PubMedGoogle Scholar
  92. 92.
    Seidl R, Fang-Kircher S, Bidmon B, Cairns N, Lubec G (1999) Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome. Neurosci Lett 260(1):9–12PubMedCrossRefGoogle Scholar
  93. 93.
    Hansen R, Oren M (1997) p53; from inductive signal to cellular effect. Curr Opin Genet Dev 7:46–51PubMedCrossRefGoogle Scholar
  94. 94.
    Rowen S, Fisher DE (1997) Mechanisms of apoptotic cell death. Leukemia 11:457–465CrossRefGoogle Scholar
  95. 95.
    Sawa A, Oyama F, Cairns N, Amano N, Matsushita M (1997) Aberrant expression of bcl-2 gene family in Down′s syndrome brains. Mol Brain Res 48:53–59PubMedCrossRefGoogle Scholar
  96. 96.
    Nagy ZS, Eisiri MM (1997) Apoptosis-related protein expression in the hippocampus in Alzheimer’s disease. Neurobiol Aging 18:565–571PubMedCrossRefGoogle Scholar
  97. 97.
    Yoshioka K, amamoto S, Moriguchi N, Miyata H, Tsukiyama K, Isokawa S, Horiuchi F, Takemura T (2000) Overexpression of Bcl-2 in transient abnormal myleopoiesis associated with Down syndrome. Ann Hematol 79:319–321PubMedCrossRefGoogle Scholar
  98. 98.
    Engidawork E, Gulesserian T, Seild R, Cairns N, Lubec G (2001) Expression of apoptosis related proteins: RAIDD, ZIP kinase, Bim/BOD, p21, Bcl-2 and NF-kB in brains of patients with Down syndrome. J Neural Transm Suppl 61:181–192PubMedGoogle Scholar
  99. 99.
    Hewitt CA, Ling KH, Merson TD, Simpson KM, Ritchie ME, King SL, Pritchard MA, Smyth GK, Thomas T, Scott HS, Voss AK (2010) Gene network disruptions and neurogenesis defects in the adult Ts1Cje mouse model of Down syndrome. PLoS One 5:e11561PubMedCrossRefGoogle Scholar
  100. 100.
    Rueda N, Flórez J, Martínez-Cué C (2011) The Ts65Dn mouse model of Down syndrome shows reduced expression of the Bcl-Xl antiapoptotic protein in the hippocampus not accompanied by changes in molecular or cellular markers of cell death. Int J Dev Neurosci 29:711–716PubMedCrossRefGoogle Scholar
  101. 101.
    Bianchi P, Ciani E, Contestabile A, Guidi S, Bartesaghi R (2010) Lithium restores neurogenesis in the subventricular zone of the Ts65Dn mouse, a model for Down syndrome. Brain Pathol 20:106–118PubMedCrossRefGoogle Scholar
  102. 102.
    Lott IT (2012) Antioxidants in Down syndrome. Biochem Biophys Acta 1822:657–663PubMedCrossRefGoogle Scholar
  103. 103.
    Kinnula VL, Crapo JD (2003) Supeoroxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med 167:1600–1619PubMedCrossRefGoogle Scholar
  104. 104.
    Vogt M, Bauer MK, Ferrari D, Schulze-Osthoff K (1998) Oxidative stress and hypoxia/reoxygenation trigger CD95 (APO-1/Fas) ligand expression in microglial cells. FEBS Lett 429:67–72PubMedCrossRefGoogle Scholar
  105. 105.
    Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967PubMedCrossRefGoogle Scholar
  106. 106.
    Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389(6648):300–305PubMedCrossRefGoogle Scholar
  107. 107.
    Kim SH, Yoo BC, Broers JL, Cairns N, Lubec G (2000) Neuroendocrine-specific protein C, a marker of neuronal differentiation, is reduced in brain of patients with Down syndrome and Alzheimer’s disease. Biochem Biophys Res Commun 276:329–334PubMedCrossRefGoogle Scholar
  108. 108.
    Kedziora J, Bartosz G (1988) Down’s syndrome: a pathology involving the lack of balance of reactive oxygen species. Free Radic Biol Med 4:317–330PubMedCrossRefGoogle Scholar
  109. 109.
    De Haan JB, Wolvetang EJ, Cristiano F, Ianello R, Bladier C, Kelner M et al (1997) Reactive oxygen species and their contribution to pathology in Down syndrome. Adv Pharmacol 38:379–402PubMedCrossRefGoogle Scholar
  110. 110.
    Busciglio J, Andersen JK, Schipper HM, Gilad GM, McCarty R, Marzatico et al (1998) Stress, aging, and neurodegenerative disorders. Molecular mechanisms. Ann N Y Acad Sci 851:429–443PubMedCrossRefGoogle Scholar
  111. 111.
    Busciglio J, Pelsman A, Helguera P, Ashur-Fabian O, Pinhasov A, Brenneman DE, Gozes I (2007) NAP and ADNF-9 protect normal and Down’s syndrome cortical neurons from oxidative damage and apoptosis. Curr Pharm Des 13(11):1091–1098PubMedCrossRefGoogle Scholar
  112. 112.
    Ellis JM, Tan HK, Gilbert RE, Muller DPR, Henley W, Moy R, Pumphrey R, Ani C, Davies S, Edwards V, Green H, Salt A, Logan S (2008) Supplementation with antioxidants and folinic acid for children with Down’s syndrome: randomised controlled trial. Br Med J 336:594–597CrossRefGoogle Scholar
  113. 113.
    Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL (2011) Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet 155:1939–1948CrossRefGoogle Scholar
  114. 114.
    Salman MS (2002) Systematic review of the effect of the therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. Eur J Paediatr Neurol 6:213–219PubMedCrossRefGoogle Scholar
  115. 115.
    Seo H, Isacson O (2005) Abnormal APP, cholinergic and cognitive function in Ts65Dn Down’s model mice. Exp Neurol 193:469–480PubMedCrossRefGoogle Scholar
  116. 116.
    Netzer WJ, Powell C, Nong Y, Blundell J, Wong L, Duff K, Flajolet M, Greengard P (2010) Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One 5:e10943PubMedCrossRefGoogle Scholar
  117. 117.
    Millan Sanchez M, Heyn SN, Das D, Moghadam S, Martin KJ, Salehi A (2011) Neurobiological elements of cognitive dysfunction in Down syndrome: exploring the role of APP. Biol Psychiatry 71(5):403–409PubMedCrossRefGoogle Scholar
  118. 118.
    Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364PubMedCrossRefGoogle Scholar
  119. 119.
    Mattson MP, Partin J, Begley JG (1998) Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 807:167–176PubMedCrossRefGoogle Scholar
  120. 120.
    Chen YZ (2004) APP induces neuronal apoptosis through APP-BP1-mediated downregulation of beta-catenin. Apoptosis 9:415–422PubMedCrossRefGoogle Scholar
  121. 121.
    Pellegrini L, Passer BJ, Tabaton M, Ganjei JK, D’Adamio L (1999) Alternative, non-secretase processing of Alzheimer’s beta-amyloid precursor protein during apoptosis by caspase-6 and -8. J Biol Chem 274:21011–21016PubMedCrossRefGoogle Scholar
  122. 122.
    Arriagada C, Bustamante M, Atwater I, Rojas E, Caviedes R, Caviedes P (2010) Apoptosis is directly related to intracelular amyloid accumulation in a cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down syndrome. Neurosci Lett 470:81–85PubMedCrossRefGoogle Scholar
  123. 123.
    Opazo P, Saud K, de Pierre Saint M, Cárdenas AM, Allen DD, Segura J, Caviedes R, Caviedes P (2006) Knockdown of amyloid precursor protein normalizes cholinergic function in a cell line derived from the cerebral cortex of a trisomy 16 mouse: an animal model of Down syndrome. J Neurosci Res 84:1303–1310PubMedCrossRefGoogle Scholar
  124. 124.
    Rojas G, Cárdenas AM, Fernández-Olivares P, Shimahara T, Segura-Aguilar J, Caviedes R, Caviedes P (2008) Effect of the knockdown of amyloid precursor protein on intracellular calcium incerases in a neuronal cell line derived from the cerebral cortx of a trisomy 16 mouse. Exp Neurol 209:234–242PubMedCrossRefGoogle Scholar
  125. 125.
    Guedj F, Lpes Pereira P, Najas S, Barallobre MJ, Chabert C, Souchet B, Sebrie C, Verney C, Herault Y, Arbones M, Delabar JM (2012) DYRK1A: a master regulatory protein controlling brain growth. Neurobiol Dis 46:190–203PubMedCrossRefGoogle Scholar
  126. 126.
    Park J, Oh Y, Yoo L, Jung MS, Song WJ, Lee SH, Seo H, Chung KC (2010) Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. J Biol Chem 285:31895–31906PubMedCrossRefGoogle Scholar
  127. 127.
    Ryoo SR, Cho HJ, Lee HW, Jeong HK, Radnaabazar C, Kim YS, Kim M, Son MY, Seo H, Chung SH et al (2008) Dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease. J Neurochem 104:1333–1344PubMedCrossRefGoogle Scholar
  128. 128.
    Wolvetang EJ, Wilson TJ, Sanij E, Busciglio J, Hatzistavrou T, Seth A, Hertzog PJ, Kola I (2003) ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Hum Mol Genet 12:247–255PubMedCrossRefGoogle Scholar
  129. 129.
    Sanij E, Hatzistavrou T, Herzog P, Kola I, Wolvetang EJ (2001) Ets2 is induced by oxidative stress and sensitizes cells to H2O2-induced apoptosis: implications for Down’s syndrome. Biochem Biophys Res Commun 287:1003–1008PubMedCrossRefGoogle Scholar
  130. 130.
    Semetchenko VI, Watson DK (2000) Ets target genes: past, present and future. Oncogene 19:6533–6548CrossRefGoogle Scholar
  131. 131.
    Courage ML, Adams RJ, Reyno S, Kwa PG (1994) Visual acuity in infants and children with Down syndrome. Dev Med Child Neurol 36:586–593PubMedCrossRefGoogle Scholar
  132. 132.
    John FM, Bromham NR, Woodhouse JM, Candy TR (2004) Spatial vision deficits in infants and children with Down syndrome. Invest Ophtalmol Vis Sci 45:1566–1572CrossRefGoogle Scholar
  133. 133.
    Little JA, Woodhouse JM, Lauritzen JS, Saunders KJ (2007) The impact of optical factors on resolution acuity in children with Down syndrome. Invest Ophtalmol Vis Sci 48:3995–4001CrossRefGoogle Scholar
  134. 134.
    Young RW (1984) Cell death during differentiation of the retina in the mouse. J Comp Neurol 229:362–373PubMedCrossRefGoogle Scholar
  135. 135.
    Boya P, de la Rosa EJ (2005) Cell death in early neural life. Birth Defects Res C 75:281–293CrossRefGoogle Scholar
  136. 136.
    Cellerino A, Bahr M, Isenmann S (2000) Apoptosis in the developing visual system. Cell Tissue Res 301:53–69PubMedCrossRefGoogle Scholar
  137. 137.
    Laguna A, aranda S, Barallobre MJ, Barhoum R, Fernández E, Fotaki V, Delabar JM, de La Luna S, de La Villa P, Arbonés ML (2008) The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development. Dev Cell 15:841–853PubMedCrossRefGoogle Scholar
  138. 138.
    Segal DJ, McCoy EE (1974) Studies on Down’s syndrome in tissue culture. I Growth rates and protein contents of fibroblasts cultures. J Cell Physiol 83:85–90PubMedCrossRefGoogle Scholar
  139. 139.
    De Haan JB, Cristiano F, Ianello R, Bladier C, Kelner MJ, Kola I (1996) Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidise activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum Mol Genet 5:283–292PubMedCrossRefGoogle Scholar
  140. 140.
    De Haan JB, Susil B, Pritchard M, Kola I (2003) An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the ‘gene dosage effect’ hypothesis. J Neural Transm Suppl 67:67–83PubMedCrossRefGoogle Scholar
  141. 141.
    Contestabile A, Fila T, Cappellini A, Bartesaghi R, Ciani E (2009) Widespread impairment of cell proliferation in the neonate Ts65Dn mouse, a model for Down syndrome. Cell Prolif 42:171–181PubMedCrossRefGoogle Scholar
  142. 142.
    Garcia-Ramírez M, Toran N, Carrascosa A, Audi L (1998) Down’s syndrome: altered chondrogenesis in fetal rib. Pediatr Res 44:93–98PubMedCrossRefGoogle Scholar
  143. 143.
    Raouf A, Seth A (2000) Ets transcription factors and targets in osteogenesis. Oncogene 19:6455–6463PubMedCrossRefGoogle Scholar
  144. 144.
    Ferreti E, Villaescusa JC, Di Rosa P, Fernández- Diaz LC, Ferrari G et al (2006) Hymoporphic mutations of the TALE gene Prep1 (pKnox1) causes a major reduction of PBx and Meis proteins and a pleiotropic embryonic phenotype. Moll Cell Biol 26:5650–5662CrossRefGoogle Scholar
  145. 145.
    Oriente F, Fernández-Díaz LC, Miele C, Iovino S, Mori S, Diaz VM, Troncone G, Cassese A, Formisano P, Blasi F et al (2008) Prep1 deficiency induces protection from diabetes and increased insulin sensitivity through a p160-mediated mechanisms. Mol Cell Biol 28:5634–5645PubMedCrossRefGoogle Scholar
  146. 146.
    Berthelsen J, Viggiano L, Schulz H, Ferretti E, Consalez GG, Rocchi M, Blasi F (1998) PKNOX1, a gene encoding PREP1, a new regulator of Pbx activity, maps on human chromosome 21q22.3 and murine chromosome 17B/C. Genomics 47:323–324PubMedCrossRefGoogle Scholar
  147. 147.
    Micali N, Ferrai C, Fernández-Díaz LC, Blasi F, Crippa MP (2009) Prep1 directly regulates the intrinsic apoptotic pathway by controlling Bcl-XL levels. Mol Cell Biol 29:1143–1151PubMedCrossRefGoogle Scholar
  148. 148.
    Micali N, Longobardi E, Lotti G, Ferrai C, Castagnaro L, Ricciardi M, Blasi F, Crippa MP (2010) Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress. Nuclei Acids Res 38:3595–3604CrossRefGoogle Scholar
  149. 149.
    Ferencz C, Neill CA, Boughman JA, Rubin JD, Brenner JI, Perry LW (1989) Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J Pediatr 114:79–86PubMedCrossRefGoogle Scholar
  150. 150.
    Carmi R, Boughman JA, Ferencz C (1992) Endocardial cushion defect: further studies of “isolated” versus “syndromic” occurrence. Am J Med Genet 43:569–575PubMedCrossRefGoogle Scholar
  151. 151.
    Hurle JM, Ojeda JL (1979) Cell death during the development of the truncus and conus of the chick embryo heart. J Anat 129(2):427–439PubMedGoogle Scholar
  152. 152.
    Kajstura J, Mansukhani M, Cheng W, Reiss K, Krajewski S, Reed JC et al (1995) Programmed cell death and expression of the protooncogen bcl-2 in myocytes during postnatal maturation of the heart. Exp Cell Res 219:110–121PubMedCrossRefGoogle Scholar
  153. 153.
    James TN (1994) Normal and abnormal consequences of apoptosis in the human heart: from postnatal morphogenesis to paroxysmal arrhythmias. Circulation 90:556–573PubMedCrossRefGoogle Scholar
  154. 154.
    James TN, St Martin E, Willis PW, Lohr TO (1996) Apoptosis as a possible cause of gradual development of complete heart block and fatal arrhthmias associated with absence of the AV node, sinus node and, intermodal pathways. Circulation 93:1424–1428PubMedCrossRefGoogle Scholar
  155. 155.
    Saphier CJ, Yeh J (1998) Altered apoptosis levels in hearts of human fetuses with Down syndrome. Am J Obstet Gynecol 179:962–965PubMedCrossRefGoogle Scholar
  156. 156.
    Hiltgen GG, Markwald RR, Litke LL (1996) Morphogenetic alterations during endocardial cushion development in the trisomy 16 Down syndrome mouse. Pediatr Cardiol 17:21–30PubMedCrossRefGoogle Scholar
  157. 157.
    Mc Dowell KM, Craven DI (2011) Pulmonary complications of Down syndrome during childhood. J Pediatr 158:319–325CrossRefGoogle Scholar
  158. 158.
    Bruijn M, von der Thüsen JH, van der Loos CM, de Kruger RR, van Loenhout RB, Bos AP, van Woensen JBM (2007) Pulmonary epithelial apoptosis in fetal Down syndrome: not higher than normal. Pediatr Dev Pathol 15:199–205CrossRefGoogle Scholar
  159. 159.
    Matute-Bello G, Martin TR (2003) Apoptosis in acute lung injury. Crit Care 7:355–358PubMedCrossRefGoogle Scholar
  160. 160.
    Kusters MA, Verstegen RH, Gemen EF et al (2009) Intrinsic defect of the immune system in children with Down syndrome. A review. Clin Exp Immunol 156:189–193PubMedCrossRefGoogle Scholar
  161. 161.
    Larocca LM, Piatelli M, Valitutti S, Castellino F, Maggiano N, Musiani P (1988) Alterations in thymocyte subpopulations in Down’s syndrome (trisomy 21). Clin Immunol Immunopathol 49:175–186PubMedCrossRefGoogle Scholar
  162. 162.
    Murphy M, Epstein LB (1992) Down’s syndrome (DS) peripheral blood: evidence for an inefficient release of mature T cells by the DS thumus. Clin Immunol Immunopathol 62:245–251PubMedCrossRefGoogle Scholar
  163. 163.
    Murphy M, Friend DS, Pike-Nobile L, Epstein LB (1992) Tumor necrosis-alfa factor and IFN-gamma expression in human thymus: localization and overexpression in Down’s syndrome (trisomy 21). J Immunol 149:2506–2512PubMedGoogle Scholar
  164. 164.
    De Hingh YC, van der Vossen PW, Gemen EF et al (2005) Intrinsic abnormalities of lymphocyte counts in children with Down syndrome. J Pediatr 147:744–747PubMedCrossRefGoogle Scholar
  165. 165.
    Gemen EFA, Verstegen RHF, Leuvenink J, de Vries E (2012) Increased circlulating apoptotic lymphocytes in children with Down syndrome. Pediatr Blood Cancer 59:1310–1312PubMedCrossRefGoogle Scholar
  166. 166.
    Bloemers BL, Bont L, de Weger RA, Otto SA, Borghans JA, Tesselaar K (2011) Decreased thymic ouput accounts for decreased naïve T cell numbers in children with Down syndrome. J Immunol 186:4500–4507PubMedCrossRefGoogle Scholar
  167. 167.
    Elsayed SM, Elsayed GM (2009) Phenotype of apoptotic lymphocytes in children with Down syndrome. Immun Ageing 6:2PubMedCrossRefGoogle Scholar
  168. 168.
    Corsi MM, Ponti W, Venditti A et al (2003) Proapoptotic activated T-cells in the blood of children with Down’s syndrome: relationship with dietary antigens and intestinal alterations. Int J Tissue React 25:117–125PubMedGoogle Scholar
  169. 169.
    Antonucci A, Di Baldassarre A, Di Giacomo F et al (1997) Detection of apoptosis in peripheral blood cells of 31 subjects affected by Down syndrome before and after zinc therapy. Ultrastruct Pathol 21:449–452PubMedCrossRefGoogle Scholar
  170. 170.
    Epstein CJ, Hofmeister BG, Yee D et al (1985) Stem cell deficiencies and thymic abnormalities in fetal mouse trisomy 16. J Exp Med 162:695–712PubMedCrossRefGoogle Scholar
  171. 171.
    Jablonska B, Ford D, Trisler D, Pessac B (2006) The growth capacity of bone marrow CD34 positve cells in culture is drastically rduced in a murine model of Down syndrome. C R Biol 329:726–732PubMedCrossRefGoogle Scholar
  172. 172.
    Peled-Kamar M, Lotem J, Okon E, Sachs L, Groner Y (1995) Thymic abnormalities and enhanced apoptosis of thymocytes an bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down’s syndrome. EMBO J 14:4985–4993PubMedGoogle Scholar
  173. 173.
    Nabarra B, Casanova M, Paris D, Nicole A, Toyama K, Sinet P-M, Ceballos I, London J (1996) Transgenic mice overexpressing the human Cu/Zn-SOD gene: ultrastructural studies of a premature thymic involution model of Down’s syndrome (trisomy 21). Lab Invest 74:617–626PubMedGoogle Scholar
  174. 174.
    Seth A, Watson DK, Blair DG, Papas TS (1989) c-ets-2 protooncogene has mitogenic and oncogenic activity. Proc Natl Acad Sci USA 86:7833–7837PubMedCrossRefGoogle Scholar
  175. 175.
    Remy P, Baltzinger M (2000) The Ets-transcription factor family in embryonic development: lessons from the amphibian and bird. Oncogene 19:6417–6431PubMedCrossRefGoogle Scholar
  176. 176.
    Maroulakou IG, Bowe DB (2000) Expression and function of Ets transcription factors in mammalian development: a regulatory network. Oncogene 19:6432–6442PubMedCrossRefGoogle Scholar
  177. 177.
    Taub JW (2001) Relationship of chromosome 21 and acute leukemia in children with Down syndrome. J Pediatr Hematol Oncol 23:175–178PubMedCrossRefGoogle Scholar
  178. 178.
    Zipursky A, Thorner P, De Harven F, Christensen H, Doyle J (1994) Myelodysplasia and acute megakaryoblastic lekemia in Down’s syndrome. Leuk Res 18:163–171PubMedCrossRefGoogle Scholar
  179. 179.
    Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM et al (2008) Abnormalities in the mieloide progenitor compartment in Down syndromefetal liver preced acquisition of GATA1 mutations. Blood 112:4507–4511PubMedCrossRefGoogle Scholar
  180. 180.
    Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A et al (2008) Trisomy 21 enhances human fetal crythro-megakaryocytic development. Blood 112:4503–4506PubMedCrossRefGoogle Scholar
  181. 181.
    Wechsler J, Green M, McDevitt MA, anastasi J, Karp JE et al (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32:148–152PubMedCrossRefGoogle Scholar
  182. 182.
    Inaba H, Londero M, Maurer SH, Oneiu M, Ge Y et al (2011) Acute megakaryoblastic leukemia without GATA1 mutation after transient mycloproliferative disorder in an infant without Down syndrome. J Clin Oncol 29:230–233CrossRefGoogle Scholar
  183. 183.
    Ge Y, LaFiura KM, Dombkowski AA, Chen Q, Payton SG, Buck SA, Salagrama S, Diakiw AE, Matherly LH, Taub JW (2008) The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 22:521–529PubMedCrossRefGoogle Scholar
  184. 184.
    Stankiewicz MJ, Crispino JD (2009) ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 113:3337–3347PubMedCrossRefGoogle Scholar
  185. 185.
    Birgerr Y, Izraeku S (2012) DYRK1A in Down syndrome: an oncogene or tumor suppressor? J Clin Invest 122:807–810CrossRefGoogle Scholar
  186. 186.
    Malinge S, Bliss-Moreau M, Kirsammer G, Diebold L, Chlon T, Gurbuxani S, Crispino JD (2012) Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome. J Clin Invest 122:948–962PubMedCrossRefGoogle Scholar
  187. 187.
    Xavier AC, Edwards H, Dombkowski AA, Tugce BB, Berman JN, Dellaire G, Xie C, Buck S, Matherly LH, Ge Y, Taub JW (2011) A unique role of GATA1s in Down syndrome acute megakaryocytic leukemia biology and therapy. PLoS One 6:e27486PubMedCrossRefGoogle Scholar
  188. 188.
    Satge D, Sommelet D, Geneix A, Nishi M, Malet P, Vekemans MA (1998) Tumor profile in Down syndrome. Am J Med Genet 78:207–216PubMedCrossRefGoogle Scholar
  189. 189.
    Hasle H, Clemmensen IH, Mikkelsen M (2000) Risks of leukaemia an solid tumours in individuals with Down’s syndrome. Am J Med Genet 78:207–216Google Scholar
  190. 190.
    Sussan TE, Yang A, Li F, Ostrowski MC, Reeves RH (2008) Trisomy represses ApcMin-mediated tumours in mouse models of Down’s syndrome. Nature 451:73–75PubMedCrossRefGoogle Scholar
  191. 191.
    Yang A, Reeves RH (2011) Increased survival following tumorigenesis in Ts65Dn mice that model Down syndrome. Cancer Res 71:3573–3581PubMedCrossRefGoogle Scholar
  192. 192.
    Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S (2009) Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459:1126–1130PubMedCrossRefGoogle Scholar
  193. 193.
    DeYoung MP, Tress M, Narayanan R (2003) Identification of Down’s syndrome critical locus gene Sim2-s as a drug therapy target for solid tumors. Proc Natl Acad Sci USA 100:4760–4765PubMedCrossRefGoogle Scholar
  194. 194.
    Chang H-S, Lin C-H, Yang C-H, Yen M-S, Lai C-R, Chen Y-R, Liang Y-J, Yu WCY (2007) Increased expression of Dyrk1a in HPV16 immortalized keratinocytes enable evasion of apoptosis. Int J Cancer 120:2377–2385PubMedCrossRefGoogle Scholar
  195. 195.
    De Wit NJ, urscher HJ, Weidle UH, Ruiter DJ, van Muijen GN (2002) Differentially expressed genes identified in human melanoma cell lines with different metastatic behaviour using high densiy oligonucleotide arrays. Melanoma Res 12:57–69PubMedCrossRefGoogle Scholar
  196. 196.
    Friedman E (2007) Mirk/Dyrk1B in cancer. J Cell Biochem 102:274–279PubMedCrossRefGoogle Scholar
  197. 197.
    Seifert A, Allan LA, Clarke PR (2008) DYRK1A phosphorylates caspase 9 at an inhibitory site and is potently inhibited in human cells by harmine. FEBS J 275:6268–6280PubMedCrossRefGoogle Scholar
  198. 198.
    Guo X, Williams JG, Schug TT, Li X (2010) DYRK1A and DYRK3 promotecell survival and phosphorylation and activation of SIRT1. J Biol Chem 285:13223–13232PubMedCrossRefGoogle Scholar
  199. 199.
    Sethypathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS, Hatzigeorgiour AG, Antonarakis SE (2007) Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untarnslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet 81:405–413CrossRefGoogle Scholar
  200. 200.
    Kuhn DE, Nuovo GJ, Martin MM, Malana GE, Pleister AP, Jiang J, Schmittgen TS, Terry AV, Gardiner K, Head E, Feldman DS, Elton TS (2008) Human chromosome 21-derived miRNAs are overexpressed in Down syndrome brains and harts. Biochem Biophys Res Commun 370:473–477PubMedCrossRefGoogle Scholar
  201. 201.
    Kuhn DE, Nuovo GJ, Terry AV, Martin MM, Malana GE, Sansom SE, Pleister AP, Beck WE, Head E, Feldman DS, Elton TS (2010) Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains. J Biol Chem 285:1529–1543PubMedCrossRefGoogle Scholar
  202. 202.
    Bushati N, Cohen SM (2007) MicroRNA functions. Annu Rev Cell Dev Biol 23:175–205PubMedCrossRefGoogle Scholar
  203. 203.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCrossRefGoogle Scholar
  204. 204.
    Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931–1934PubMedCrossRefGoogle Scholar
  205. 205.
    Zhang Y, Liao J-M, Zeng SX, Lu H (2011) p53 downregulates Down syndrome-associated DYRK1A through miR-1246. EMBO Rep 12:811–817PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Noemí Rueda
    • 1
  • Jesús Flórez
    • 1
  • Carmen Martínez-Cué
    • 1
  1. 1.Department of Physiology and PharmacologyFaculty of Medicine University of CantabriaSantanderSpain

Personalised recommendations