Alteration of gene expression in Down’s syndrome (DS) brains: its significance in neurodegeneration



Several groups have reported pro-apoptotic alteration of gene expression in Down’s syndrome (DS) brains. Aged DS brains manifest a similar neuropathology to Alzheimer’s disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although it is controversial if neurodegenerative processes play a pathological role in DS brains, evidence such as cortical neurons from fetal DS brains showing vulnerability to cell death when compared with neurons from control subjects supports this point of view.

In this chapter, we review the reports that demonstrate pro-apoptotic alteration of gene expression in DS brains. In addition to the pathogenic genes on chromosome 21, such as amyloid precursor protein (APP) and CuZn-superoxide dismutase (SOD1), other genes which associate with p53, or with processes for protein folding have been frequently found.


Amyotrophic Lateral Sclerosis Down Syndrome Neuronal Cell Death Senile Plaque 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.



Alzheimer’s disease


aldehyde dehydrogenase


amyotrophic lateral sclerosis


amyloid precursor protein


Down’s syndrome


enzyme linked immunosorbent assay


glyceraldehyde-3-phosphate dehydrogenase


glutathione peroxidase


Jun N-terminal kinase


messenger RNA


neuronal apoptosis inhibitory protein


neurofibrillary tangle


p53 induced genes


reactive oxygen species


reverse trascriptase-coupled polymerase chain reaction


serial analysis of gene expression


superoxide dismutase


senile plaque


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  1. Brooksbank BW, Balazs R (1984) Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down’s syndrome fetal brain. Brain Res 318: 37–44PubMedGoogle Scholar
  2. 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
  3. Celis JE, Kruhoffer M, Gromova I, Frederiksen C, Ostergaard M, Thykjaer T, Gromov P,Yu J, Palsdottir H, Magnusson N, Orntoft TF (2000) Gene expression profiling:monitoring transcription and translation products using DNA microarrays and proteomics. FEBS Lett 480: 2–16PubMedCrossRefGoogle Scholar
  4. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A,Rossor M, Roques P, Hardy J, et al (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353: 844–846PubMedCrossRefGoogle Scholar
  5. Coyle JT, Oster-Granite ML, Gearhart JD (1986) The neurobiologic consequences of Down syndrome. Brain Res Bull 16: 773–787PubMedCrossRefGoogle Scholar
  6. 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
  7. 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
  8. de la Monte SM (1999) Molecular abnormalities of the brain in Down syndrome:relevance to Alzheimer’s neurodegeneration. J Neural Transm [Suppl] 57: 1–19Google Scholar
  9. 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
  10. Fountoulakis M, Cairns N, Lubec G (1999) Increased levels of 14-3-3 gamma and epsilon proteins in brain of patients with Alzheimer’s disease and Down syndrome. J Neural Transm [Suppl] 57: 323–335Google Scholar
  11. Fountoulakis M, Hardmeier R, Höger H, Lubec G (2001) Postmortem changes in the level of brain proteins. Exp Neurol 167: 86–94PubMedCrossRefGoogle Scholar
  12. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T,Clemens J, Donaldson T, Gillespie F, et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527PubMedCrossRefGoogle Scholar
  13. 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
  14. Greber-Platzer S, Balcz B, Cairns N, Lubec G (1999) c-fos expression in brains of patients with Down syndrome. J Neural Transm [Suppl] 57: 75–85Google Scholar
  15. Gulesserian T, Seidl R, Hardmeier R, Cairns N, Lubec G (2001) Superoxide dismutase SOD1, encoded on chromosome 21, but not SOD2 is overexpressed in brains of patients with Down syndrome. J Invest Med 49: 41–46CrossRefGoogle Scholar
  16. 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
  17. Iannello RC, Crack PJ, de Haan JB, Kola I (1999) Oxidative stress and neural dysfunction in Down syndrome. J Neural Transm [Suppl] 57: 257–267Google Scholar
  18. 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
  19. 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
  20. Kitzmueller E, Labudova O, Rink H, Cairns N, Lubec G (1999) Altered gene expression in fetal Down syndrome brain as revealed by the gene hunting technique of subtractive hybridization. J Neural Transm [Suppl] 57: 99–124Google Scholar
  21. Krapfenbauer K, Yoo BC, Cairns N, Lubec G (1999) Differential display reveals deteriorated mRNA levels of NADH3 (complex I) in cerebellum of patients with Down syndrome. J Neural Transm [Suppl] 57: 211–220Google Scholar
  22. 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
  23. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G (1995) The Alzheimer’s A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genet 9: 21–30PubMedCrossRefGoogle Scholar
  24. Liang P, Pardee AB (1992) Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257: 967–971PubMedCrossRefGoogle Scholar
  25. Lubec G, Labudova O, Cairns N, Berndt P, Langen H, Fountoulakis M (1999a) Reduced aldehyde dehydrogenase levels in the brain of patients with Down syndrome. J Neural Transm [Suppl] 57: 21–40Google Scholar
  26. Lubec G, Labudova O, Cairns N, Fountoulakis M (1999b) Increased glyceraldehyde 3-phosphate dehydrogenase levels in the brain of patients with Down’s syndrome. Neurosci Lett 260: 141–145PubMedCrossRefGoogle Scholar
  27. Mann DM (1988) The pathological association between Down syndrome and Alzheimer disease. Mech Ageing Dev 43: 99–136PubMedCrossRefGoogle Scholar
  28. 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
  29. Morrison RS, Kinoshita Y (2000) The role of p53 in neuronal cell death. Cell Death Differ 7: 868–879PubMedCrossRefGoogle Scholar
  30. Oyama F, Cairns 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
  31. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389: 300–305PubMedCrossRefGoogle Scholar
  32. 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
  33. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62PubMedCrossRefGoogle Scholar
  34. Sawa A (1999b) Neuronal cell death in Down’s syndrome. J Neural Transm [Suppl] 57: 87–97Google Scholar
  35. Sawa A, Khan AA, Hester LD, Snyder SH (1997a) Glyceraldehyde-3-phosphate dehydrogenase: nuclear translocation participates in neuronal and nonneuronal cell death. Proc Natl Acad Sci USA 94: 11669–11674PubMedCrossRefGoogle Scholar
  36. Sawa A, Oyama F, Cairns NJ, Amano N, Matsushita M (1997b) Aberrant expression of bcl-2 gene family in Down’s syndrome brains. Brain Res Mol Brain Res 48: 53–59PubMedCrossRefGoogle Scholar
  37. Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler Jr JF, Greenamyer JT, Snyder SH, Ross CA (1999a) Increased apoptosis of Huntington’s disease lymphoblasts associated with repeat lengh-dependent mitochondrial depolarization. Nature Med 5: 1194–1198PubMedCrossRefGoogle Scholar
  38. Schatzmann-Turhani D, Labudova O, Yeghiazaryan K, Rink H, Hauser E, Cairns N, Lubec G (1999) Overexpression of DNAse I in brain of patients with Down syndrome. J Neural Transm [Suppl] 57: 353–362Google Scholar
  39. Seidl R, Bajo M, Bohm K, LaCasse EC, MacKenzie AE, Cairns N, Lubec G (1999a) Neuronal apoptosis inhibitory protein (NAIP)-like immunoreactivity in brains of adult patients with Down syndrome. J Neural Transm [Suppl] 57: 283–291Google Scholar
  40. Seidl R, Fang-Kircher S, Bidmon B, Cairns N, Lubec G (1999b) Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome. Neurosci Lett 260: 9–12PubMedCrossRefGoogle Scholar
  41. 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
  42. Velculescu VE, Zhang L, Vogelstein B, Kinzler KW (1995) Serial analysis of gene expression. Science 270: 484–487PubMedCrossRefGoogle Scholar
  43. Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet 23: 425–428PubMedCrossRefGoogle Scholar
  44. 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
  45. 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
  46. Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245: 417–420PubMedCrossRefGoogle Scholar
  47. Yoo BC, Seidl R, Cairns N, Lubec G (1999) Heat-shock protein 70 levels in brain of patients with Down syndrome and Alzheimer’s disease. J Neural Transm [Suppl] 57: 315–322Google Scholar
  48. 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 2001

Authors and Affiliations

  • A. Sawa
    • 1
  1. 1.Department of Psychiatry and Behavioral Sciences, Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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