Advertisement

Down syndrome: a model for the study of Alzheimer’s disease and aging

  • J. M. Delabar
  • J. L. Blouin
  • Z. Rahmani
  • N. Créau-Goldberg
  • Z. Chettouh
  • A. Nicole
  • A. Bruel
  • M. C. de Blois
  • P. M. Sinet
Part of the New Vistas in Drug Research book series (DRUG RESEARCH, volume 1)

Summary

Down syndrome is defined by the association of a number of features usually observed in patients with trisomy of chromosome 21. Different forms of aneuploidy are encountered: free trisomy 21 (the most frequent), partial trisomy 21, unbalanced translocation, mosaicism, and microduplications of a short chromosomic fragment. Comparison of genotype and phenotype permitted us to define a critical region for the pathogenesis of Down syndrome, on the proximal part ar 21 q 22.3. Down syndrome is also associated with early manifestation of aging and Alzheimer like neuropathology; this pathology results from the presence of an extra copy of one or few genes on chromosome 21. We hypothesize that Alzheimer’s disease might, at least in certain patients, be secondary to a chromosome 21 defect susceptible to induce the overexpression of this or these genes. Experimental approaches for testing this hypothesis have been recently developed, both in familial and sporadic Alzheimer’s disease.

Keywords

Down Syndrome Normal Karyotype Paired Helical Filament Partial Trisomy Paired Helical Filament 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anderson BH, Breinburg D, Downes MJ, Green PJ, Tomlinson BE, Ulrich J, Wood JN, Kahn J (1982) Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature 298: 84–86CrossRefGoogle Scholar
  2. Aula P, Leisti J, von Koskull H (1973) Partial trisomy 21. Clin Genet 4: 241–251PubMedCrossRefGoogle Scholar
  3. Avraham KB, Schickler M, Sapoznikov D, Yarom R, Groner Y (1988) Down’s Syndrome: abnormal neuromuscular junction in tongue of trans-genic mice with elevated levels of human Cu-Zn superoxide dismutase. Cell 54: 823–829PubMedCrossRefGoogle Scholar
  4. Blanquet V, Goldgaber D, Turleau C, Creau-Goldberg N, Delabar JM, Sinet PM, Roudier M, de Grouchy J (1987) The B amyloid protein cDNA hybridizes in normal and Alzheimer individuals near the interface of 21 q 21 and 21 q 22. 1. Ann Genet 30: 68–69PubMedGoogle Scholar
  5. Blouin JL, Rahmani Z, Chettouh Z, Prieur M, Fermania J, Poissonnier M, Leonard C, Nicole A, Mattei JF, Sinet PM, Delabar JM (1990) Slot blot method for the quantification of DNA sequences and mapping of chromosome rearrangements: application to chromosome 21. Am J Hum Genet 46: 518–526PubMedGoogle Scholar
  6. Cantu JM, Hernandez A, Plascencia L, Vaca G, Moller M, Rivera H (1980) Partial trisomy and monosomy 21 in an infant with an unusual de novo 21/21 translocation. Ann Genet 23: 183–186PubMedGoogle Scholar
  7. Ceballos I, Delabar JM, Nicole A, Kamoun P, Sinet PM (1988) Expression of transfected human superoxide dismutase in mouse L-cells and NS20Y neuroblastoma cells induces enhancement of glutathione peroxidase activity. Biochim Biophys Acta 949: 58–64PubMedGoogle Scholar
  8. Cohen ML, Golde TE, Usiak MF, Younkin LH, Younkin SG (1988) In situ hybrization of nucleus basalis neurons shows increased B-amyloid mRNA in Alzheimer disease. Proc Natl Acad Sci USA 85: 1227–1231PubMedCrossRefGoogle Scholar
  9. Delacourte A, Defossez A, Ceballos I, Nicole A, Sinet PM (1988) Preferential localization of copper zinc superoxide dismutase in the vulnerable cortical neurons in Alzheimer’s disease. Neurosci Lett 92: 247–253PubMedCrossRefGoogle Scholar
  10. Delabar JM, Sinet PM, Chadefaux B, Nicole A, Gegonne A, Stehelin D, Fridlansky F, Creau-Goldberg N, Turleau C, Grouchy J de ( 1987 a) Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype ( Down syndrome ). Hum Genet 76: 225–229PubMedCrossRefGoogle Scholar
  11. Ceballos I, Delabar JM, Nicole A, Kamoun P, Sinet PM (1988) Expression of transfected human superoxide dismutase in mouse L-cells and NS20Y neuroblastoma cells induces enhancement of glutathione peroxidase activity. Biochim Biophys Acta 949: 58–64PubMedGoogle Scholar
  12. Delabar JM, Lamour Y, Gegonne A, Davous P, Roudier M, Ceballos I, Amouyel P, Stehelin D, Sinet PM (1986) Rearrangement of chromosome 21 in Alzheimer’s disease. Ann Genet 29: 226–228PubMedGoogle Scholar
  13. Delabar JM, Rahmani Z, Blouin JL, Nicole A, Creau-Goldberg N, Ceballos I, Grouchy J de, Huret JL, Lamour Y, Roudier M, Davous P, Sinet PM ( 1988 a) Gene dosage in Down syndrome and Alzheimer’s disease. In: Brown P, Bolis CL, Gajdusek D (eds) Discussions in neurosciences. Magistrati PJ, V: 3: 97–101Google Scholar
  14. Delabar JM, Rahmani Z, Blouin JL, Nicole A, Creau-Goldberg M, Ceballos I, Lamour Y, Roudier M, Davous P, Sinet PM ( 1988 b) Molecular analysis of patients with Alzheimer’s disease. In: Sinet PM, Lamour Y, Christen Y (eds) Research and perspectives in Alzheimer’s disease. Springer, New York, pp 151–156Google Scholar
  15. Glenner GG, Wong MD (1984) Alzheimer’s disease and Down syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Comm 122: 1131–1135PubMedCrossRefGoogle Scholar
  16. Goate AM, Haynes AR, Owen MJ (1989) Predisposing locus for AD on chromosome 21. Lancet 1: 352–355PubMedCrossRefGoogle Scholar
  17. Grouche J de, Turleau C (1982) Atlas des maladies chromosomiques. Ex-pension Scientifique Française, ParisGoogle Scholar
  18. Habedank M, Rodewald A (1982) Moderate Down’s syndrome in three siblings having partial trisomy 21 q 22.2 — gter and therefore no SOD-1 excess. Hum Genet 60: 74–77PubMedCrossRefGoogle Scholar
  19. Higgins GA, Lewis DA, Bahmanyar S, Goldgaber D, Gajdusek DC, Young WG, Morrison JH, Wilson MC (1988) Differential regulation of amyloid protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer’s disease. Proc Natl Acad Sci USA 85: 1297–1301PubMedCrossRefGoogle Scholar
  20. Huret JL, Delabar JM, Marlhens F, Aurias A, Nicole A, Berthier M, Tanzer J, Sinet P (1987) Down syndrome with duplication of a region of chromosome 21 containing the CuZn superoxide dismutase gene without detectable karyotypic abnormality. Hum Genet 75: 251–257PubMedCrossRefGoogle Scholar
  21. Jackson JF, North ER III, Thomas JG (1976) Clinical diagnosis of Down’s syndrome. Clin Genet 9: 483–487PubMedCrossRefGoogle Scholar
  22. Jenkins EC, Duncan J, Wright CE, Gordano FM, Wilbur L, Wisniewski K, Sklower SL, French JH, Jones C, Brown WT (1983) A typical Down syndrome and partial trisomy 21. Clin Genet 24: 97–102PubMedCrossRefGoogle Scholar
  23. Korenberg JR, Pulst SM, Kawashima H, Ikeuchi T, Yamamoto K, Ogasawara N, Schonberg SA, West R, Kojis T, Epstein CJ (1988) Familial Down syndrome with normal karyotype: molecular definition of the region. Am J Hum Genet 43: A0439Google Scholar
  24. Lai F, Williams R, Waltham MA (1987) Alzheimer’s dementia in Down’s syndrome. Neurology 37: 332Google Scholar
  25. Lejeune J, Gautier M, Turpin R (1959) Etude des chromosomes somatiques de neuf enfants mongoliens. C R Acad Sci Paris 248: 1721–1722PubMedGoogle Scholar
  26. Lai F, Williams R, Waltham MA (1987) Alzheimer’s dementia in Down’s syndrome. Neurology 37: 332Google Scholar
  27. Mann DM (1988) Neuropathology of Alzheimer’s disease: towards an understanding of the pathogenesis. Biochem Soc Trans 17: 73–75Google Scholar
  28. Mattei JF, Mattei MG, Beateman MA, Giraud F (1981) Trisomy 21 for the region 21 q 22.3: identification by high resolution R banding patterns. Hum Genet 56: 409–411PubMedCrossRefGoogle Scholar
  29. Palmert MR, Golde TE, Cohen ML, Kovacs DM, Tanzi RE, Gusella JF, Usiak MF, Younkin LH, Younkin SG (1988) Amyloid protein precursor messenger RNAs differential expression in Alzheimer’s disease. Science 241: 1080–1084PubMedCrossRefGoogle Scholar
  30. Park JP, Wurster-Hill DH, Andrews PA, Cooley WC, Graham JM Jr (1987) Free proximal trisomy 21 without the Down syndrome. Clin Genet 32: 342–348PubMedCrossRefGoogle Scholar
  31. Parloir C, Fryns JP, Van den Berghe (1979) Down’s syndrome in brother and sister without evident trisomy 21. Hum Genet 51: 227–230PubMedCrossRefGoogle Scholar
  32. Pericak-Vance MA, Yamaoka LN, Haynes CS (1988) Genetic linkage studies in Alzheimer disease families. Exp Neurol 102: 271–279PubMedCrossRefGoogle Scholar
  33. Podlisny MR, Lee G, Selkoe DJ (1987) Gene dosage of the amyloid B precursor protein in Alzheimer’s disease. Science 238: 669–671PubMedCrossRefGoogle Scholar
  34. Poissonier M, Saint-Paul B, Dutrillaux B, Chassaigne M, Gruyer P, BlignièresStrouk G de (1976) Trisomie 21 partielle (21 q 21–21 q 22.2). Ann Genet 19: 69–73Google Scholar
  35. Pericak-Vance MA, Yamaoka LN, Haynes CS (1988) Genetic linkage studies in Alzheimer disease families. Exp Neurol 102: 271–279PubMedCrossRefGoogle Scholar
  36. Schellenberg GD, Bird TD, Wijsman EM, Moore DK (1988) Absence of linkage of chromosome 21 q 21 markers to familial Alheimer’s disease. Science 241: 1507–1510PubMedCrossRefGoogle Scholar
  37. Sacchi N, Nalbantoglu J, Sergovich FP, Papas TS (1988) Human ETS 2 gene is not rearranged in Alzheimer disease. Proc Natl Acad Sci USA 85: 7675–7679PubMedCrossRefGoogle Scholar
  38. St Georg-Hyslop T, Tanzi R, Polinsky R, Haines JL, Nee L, Watkins PC, Myers RM, Feldman RG, Pollen D, et al (1987) The genetic defect causing familial Alzheimer disease maps on chromosome 21. Science 235: 885–890CrossRefGoogle Scholar
  39. Schellenberg GD, Bird TD, Wijsman EM, Moore DK (1988) Absence of linkage of chromosome 21 q 21 markers to familial Alheimer’s disease. Science 241: 1507–1510PubMedCrossRefGoogle Scholar
  40. Schweber M, Tuson C, Shiloh R, Ben-Neriah Z (1987) Triplication of chromosome 21 material in Alzheimer’s disease. Neurology 37 [Suppl 11: 222Google Scholar
  41. Sinet PM, Couturier J, Dutrillaux B, Poissonnier M, Raoul O, Rethoré MO, Allard D, Lejeune J, Jerome H (1976) Trisomie 21 et superoxide dismutase ( IPOA ). Exp Cell Res 97: 47–55PubMedCrossRefGoogle Scholar
  42. Sinet PM (1982) Metabolism of oxygen derivatives in Down syndrome. Ann NY Acad Sci 396: 83–94PubMedCrossRefGoogle Scholar
  43. Tanzi RE, Bird ED, Latt SA, Neve RL (1987) The amyloid protein gene is not duplicated in brains from patients with Alzheimer’s disease. Science 238: 666–669PubMedCrossRefGoogle Scholar
  44. Taylor A (1968) Cell selection in vivo in normal/G trisomie mosaics. Nature 219: 1028–1031PubMedCrossRefGoogle Scholar
  45. Uchida IA, Freeman VCP (1985) Trisomy 21 Down syndrome—Parental mosaicism. Hum Genet 70: 246–248PubMedCrossRefGoogle Scholar
  46. Schellenberg GD, Bird TD, Wijsman EM, Moore DK (1988) Absence of linkage of chromosome 21 q 21 markers to familial Alheimer’s disease. Science 241: 1507–1510PubMedCrossRefGoogle Scholar
  47. Wisniewski KE, Dalton AJ, Crapper Mc Lachlan DL, Wen GY, Wisniewski HM (1985) Alzheimer’s disease in Down’s syndrome: clinicopathological studies. Neurology 35: 957–961PubMedGoogle Scholar
  48. Wolozin B, Scicutella A, Davies P (1988) Reexpression of a developmentally regulated antigen in Down syndrome and Alzheimer’s disease. Proc Natl Acad Sci USA 85: 6202–6206PubMedCrossRefGoogle Scholar
  49. Yates CM, Simpson J, Maloney AFJ, Gorden A, Reid AH (1980) Alzheimer like cholinergic deficiency in Down syndrome. Lancet 2: 979PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1990

Authors and Affiliations

  • J. M. Delabar
    • 1
  • J. L. Blouin
    • 2
  • Z. Rahmani
    • 1
  • N. Créau-Goldberg
    • 2
  • Z. Chettouh
    • 1
  • A. Nicole
    • 1
  • A. Bruel
    • 1
  • M. C. de Blois
    • 3
  • P. M. Sinet
    • 1
  1. 1.Laboratoire de Biochimie GénétiqueURA CNRS 1335ParisFrance
  2. 2.INSERM U 173ParisFrance
  3. 3.Service de CytogénétiqueHôpital NeckerParisFrance

Personalised recommendations