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Neuronal cell death in Down’s syndrome

Conference paper

Summary

Down’s syndrome (DS), occurring in 0.8 out of 1,000 live births, is a genetic disorder in which an extra portion of chromosome 21 leads to several abnormalities. With respect to the nervous system, it causes mental retardation. It is conceived that abnormal neuronal cell death in development is involved, but there is no direct evidence yet. In addition to developmental brain abnormalities, almost all DS brains over 40 years old manifest a similar pathology to Alzheimer’s disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although there was a debate to segregate dementia from underlying mental retardation, at least some portion of DS patients exhibit deteriorated mental status with aging. The mechanism underlying these abnormalities at the molecular level remains to be elucidated. Recently there have been several reports suggesting abnormalities reflecting increased risk to apoptosis in DS brains. Increased expression of several apoptosis-related genes (p53, fas, ratio of bax to bcl-2, GAPDH) in DS brains has been reported. Cultured neurons from both patients and model animals are reportedly more vulnerable to apoptosis. Overproduction of reactive oxygen species and its causative roles for increased apoptosis in DS tissues are suggested. One possible hypothesis is an increased susceptibility to apoptosis due to p53 overactivation in DS brains. Aβ42, a critical peptide for AD pathology from amyloid precursor protein (APP), can be detected in DS brains. Aβ42 is deposited in SP from an early stage, suggesting common molecular mechanisms in DS and AD. Animal models for DS are important in the search of molecular mechanisms. Several types of models are now available. Future DS studies are expected to integrate information from animal models and human tissues.

Keywords

Down Syndrome Neuronal Cell Death Senile Plaque Apoptotic Index Ts65Dn Mouse 
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.

Abbreviations

AD

Alzheimer’s disease

APP

amyloid precursor protein

DS

Down’s syndrome

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

HD

Huntington’s disease

NFT

neurofibrillary tangle

ROS

reactive oxygen species

RT-PCR

reverse trascriptase-coupled polymerase chain reaction

SAGE

serial analysis of gene expression

SOD

superoxide dismutase

SP

senile plaque

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References

  1. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322–1326PubMedCrossRefGoogle Scholar
  2. 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: 823–829PubMedCrossRefGoogle Scholar
  3. Aylward EH, Habbak R, Warren AC, Pulsifer MB, Barta PE, Jerram M, Pearlson GD (1997) Cerebellar volume in adults with Down syndrome. Arch Neurol 54: 209–212PubMedCrossRefGoogle Scholar
  4. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P (1998) Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282: 290–293PubMedCrossRefGoogle Scholar
  5. Brooksbank BW, Balazs R (1984) Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down’s syndrome fetal brain. Brain Res 318: 37–44PubMedGoogle Scholar
  6. 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
  7. Coyle JT, Oster-Granite ML, Gearhart JD (1986) The neurobiologic consequences of Down syndrome. Brain Res Bull 16: 773–787PubMedCrossRefGoogle Scholar
  8. Coyle JT, Oster-Granite ML, Reeves RH, Gearhart JD (1988) Down syndrome, Alzheimer’s disease and the trisomy 16 mouse. Trends Neurosci 11: 390–394PubMedCrossRefGoogle Scholar
  9. Davisson MT, Schmidt C, Akeson EC (1990) Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog Clin Biol Res 360: 263–280PubMedGoogle Scholar
  10. de la Monte SM, Hedley-Whyte ET (1990) Small cerebral hemispheres in adults with Down’s syndrome: contributions of developmental arrest and lesions of Alzheimer’s disease. J Neuropathol Exp Neurol 49: 509–520PubMedCrossRefGoogle Scholar
  11. de la Monte SM, Sohn YK, Wands JR (1997) Correlates of p53-and Fas (CD95)-mediated apoptosis in Alzheimer’s disease. J Neurol Sci 152: 73–83PubMedCrossRefGoogle Scholar
  12. de la Monte SM, Sohn YK, Ganju N, Wands JR (1998) P53-and CD95-associated apoptosis in neurodegenerative diseases. Lab Invest 78: 401–411PubMedGoogle Scholar
  13. Dragunow M, Faull RL, Lawlor P, Beilharz EJ, Singleton K, Walker EB, Mee E (1995) In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobes. Neuroreport 6: 1053–1057PubMedCrossRefGoogle Scholar
  14. Epstein CJ (1986) The consequences of chromosomal imbalance. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  15. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopias S, Johnson-Wood K, Khan K, Lee M, Leibowits P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523–527PubMedCrossRefGoogle Scholar
  16. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704–706PubMedCrossRefGoogle Scholar
  17. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281: 1309–1312PubMedCrossRefGoogle Scholar
  18. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235: 877–880PubMedCrossRefGoogle Scholar
  19. Hallam DM, Maroun LE (1998) Anti-gamma interferon can prevent the premature death of trisomy 16 mouse cortical neurons in culture. Neurosci Lett 252: 17–20PubMedCrossRefGoogle Scholar
  20. Hayn M, Kremser K, Singewald N, Cairns N, Nemethova M, Lubec B, Lubec G (1996) Evidence against the involvement of reactive oxygen species in the pathogenesis of neuronal death in Down’s syndrome and Alzheimer’s disease. Life Sci 59: 537–544PubMedCrossRefGoogle Scholar
  21. Holtzman DM, Li YW, DeArmond SJ, McKinley MP, Gage FH, Epstein CJ, Mobley WC (1992) Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants. Proc Natl Acad Sci USA 89: 1383–1387PubMedCrossRefGoogle Scholar
  22. Holtzman DM, Li Y, Chen K, Gage FH, Epstein CJ, Mobley WC (1993) Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. Neurology 43: 2668–2673PubMedCrossRefGoogle Scholar
  23. Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, Johnson RM, Chen K, Sun Y, Carlson E, Alleva E, Epstein CJ, Mobley WC (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA 93: 13333–13338PubMedCrossRefGoogle Scholar
  24. Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y (1995) Amyloid beta protein (A beta) deposition: a beta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol 37: 294–299PubMedCrossRefGoogle Scholar
  25. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733–736PubMedCrossRefGoogle Scholar
  26. Labudova O, Krapfenbauer K, Moenkemann H, Rink H, Kitzmuller E, Cairns N, Lubec G (1998) Decreased transcription factor junD in brains of patients with Down syndrome. Neurosci Lett 252: 159–162PubMedCrossRefGoogle Scholar
  27. Lai F, Williams RS (1989) A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 46: 849–853PubMedCrossRefGoogle Scholar
  28. Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, Jellinger K, Wisniewski HM (1995) Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ. Acta Neuropathol 89: 35–41PubMedCrossRefGoogle Scholar
  29. Lubec G, Labudova O, Cairns N, Fountoulakis M (1999) Increased glyceraldehyde 3-phosphate dehydrogenase levels in the brain of patients with Down’s syndrome. Neurosci Lett 260: 141–145PubMedCrossRefGoogle Scholar
  30. Mann DM, Esiri MM (1988) The site of the earliest lesions of Alzheimer’s disease. N Engl J Med 318: 789–790PubMedCrossRefGoogle Scholar
  31. Mann DM, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 89:169–179PubMedCrossRefGoogle Scholar
  32. Mann DM, Iwatsubo T (1996) Diffuse plaques in the cerebellum and corpus striatum in Down’s syndrome contain amyloid beta protein (A beta) only in the form of A beta 42(43). Neurodegeneration 5: 115–120PubMedCrossRefGoogle Scholar
  33. Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct trascriptional activator of the human bax gene. Cell 80: 293–299PubMedCrossRefGoogle Scholar
  34. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188: 2033–2045PubMedCrossRefGoogle Scholar
  35. Nagy ZS, Esiri MM (1997) Apoptosis-related protein expression in the hippocampus in Alzheimer’s disease. Neurobiol Aging 18: 565–571PubMedCrossRefGoogle Scholar
  36. Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Goncalves O, Verge G, Momoli F, Welner SA, Massicotte G, Julien JP, Shapiro ML (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387: 500–505PubMedCrossRefGoogle Scholar
  37. O’Barr S, Schultz J, Rogers J (1996) Expression of the protooncogene bcl-2 in Alzheimer’s disease brain. Neurobiol Aging 17: 131–136CrossRefGoogle Scholar
  38. Oyama F, Carins NJ, Shimada H, Oyama R, Titani K, Ihara Y (1994) Down’s syndrome: up-regulation of beta amyloid protein precursor and tau mRNAs and their defective coordination. J Neurochem 62:1062–1066PubMedCrossRefGoogle Scholar
  39. Pearlson GD, Breiter SN, Aylward EH, Warren AC, Grygorcewicz M, Frangou S, Barta PE, Pulsifer MB (1998) MRI brain changes in subjects with Down syndrome with and without dementia. Dev Med Child Neurol 40: 326–334PubMedGoogle Scholar
  40. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389: 300–305PubMedCrossRefGoogle Scholar
  41. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmidt C, Bronson RT, Davisson MT (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet 11: 177–184PubMedCrossRefGoogle Scholar
  42. Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320: 1446–1452PubMedCrossRefGoogle Scholar
  43. 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: 6256–6261PubMedCrossRefGoogle Scholar
  44. Satou T, Cummings BJ, Cotman CW (1995) Immunoreactivity for Bcl-2 protein within neurons in the Alzheimer’s disease brain increases with disease severity. Brain Res 697: 35–43PubMedCrossRefGoogle Scholar
  45. Sawa A, Oyama F, Cairns NJ, Amano N, Matsushita M (1997a) Aberrant expression of bcl-2 gene family in Down’s syndrome brains. Brain Res Mol Brain Res 48: 53–59PubMedCrossRefGoogle Scholar
  46. Sawa A, Khan AA, Hester LD, Snyder SH (1997b) Glyceraldehyde-3-phosphate dehydrogenase: nuclear translocation participates in neuronal and nonneuronal cell death. Proc Natl Acad Sci USA 94: 11669–11674PubMedCrossRefGoogle Scholar
  47. Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler Jr JF, Greenamyer JT, Snyder SH, Ross CA (1999) Increased apoptosis of Huntington’s disease lymphoblasts associated with repeat lengh-dependent mitochondrial depolarization. Nature Med 5: 1194–1198PubMedCrossRefGoogle Scholar
  48. Schapiro MB, Haxby JV, Grady CL (1992) Nature of mental retardation and dementia in Down syndrome: study with PET, CT, and neuropsychology. Neurobiol Aging 13: 723–734PubMedCrossRefGoogle Scholar
  49. 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: 7216–7231PubMedGoogle Scholar
  50. 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: 9–12PubMedCrossRefGoogle Scholar
  51. Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, O’Dell TJ, Fung J, Weier HU, Cheng JF, Rubin EM (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nature Genet 16: 28–36PubMedCrossRefGoogle Scholar
  52. 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
  53. Su JH, Anderson AJ, Cummings BJ, Cotman CW (1994) Immunohistochemical evidence for apoptosis in Alzheimer’s disease. Neuroreport 5: 2529–2533PubMedCrossRefGoogle Scholar
  54. Su JH, Satou T, Anderson AJ, Cotman CW (1996) Up-regulation of Bcl-2 is associated with neuronal DNA damage in Alzheimer’s disease. Neuroreport 7: 437–440PubMedCrossRefGoogle Scholar
  55. Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235: 880–884PubMedCrossRefGoogle Scholar
  56. Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar
  57. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G (1999) The Friedrich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 8: 425–430PubMedCrossRefGoogle Scholar
  58. Yamatsuji T, Matsui T, Okamoto T, Komatsuzaki K, Takeda S, Fukumoto H, Iwatsubo T, Suzuki N, Asami-Odaka A, Ireland S, Kinane TB, Giambarella U, Nishimoto I (1996) G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer’s disease-associated mutants of APP. Science 272: 1349–1352PubMedCrossRefGoogle Scholar
  59. Yoshikawa K, Aizawa T, Hayashi Y (1992) Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359: 64–67PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • A. Sawa
    • 1
  1. 1.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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