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. 1991 Feb;10(2):297–303. doi: 10.1002/j.1460-2075.1991.tb07950.x

Transplants of mouse trisomy 16 hippocampus provide a model of Alzheimer's disease neuropathology.

S J Richards 1, J J Waters 1, K Beyreuther 1, C L Masters 1, C M Wischik 1, D R Sparkman 1, C L White III 1, C R Abraham 1, S B Dunnett 1
PMCID: PMC452646  PMID: 1899372

Abstract

Alzheimer's disease, which is characterized by amyloid plaques and neurofibrillary tangles, may be attributed to the abnormal expression of gene(s) located on human chromosome 21. Genetic linkage studies have narrowed the region of candidate genes to 21q11.2-21q22 of the long arm of this chromosome. Several single copy sequences within this region, including the amyloid precursor protein (APP), have been mapped to mouse chromosome 16. Reliable strategies exist for breeding Trisomy 16 mice. However, the consequences of developmental overexpression of genes on chromosome 16 have not been previously investigated, because of the lethal effects of this aneuploidy during gestation. In the present report, we employ neural transplantation to study long-term survival and pathogenesis in Trisomy 16 central nervous system tissues. Immunocytochemical staining with antiserum raised against the synthetic APP, beta-A4 and alpha 1-antichymotrypsin revealed numerous densely stained cells within hippocampal grafts of Trisomy 16 mice. Similarly, a population of grafted cells were positively stained following incubation with an antiserum raised against components of the pathological neurofibrillary tangle and with the monoclonal antibodies Tau 6.423 and ubiquitin.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham C. R., Selkoe D. J., Potter H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988 Feb 26;52(4):487–501. doi: 10.1016/0092-8674(88)90462-x. [DOI] [PubMed] [Google Scholar]
  2. Abraham C. R., Shirahama T., Potter H. Alpha 1-antichymotrypsin is associated solely with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha 1-antichymotrypsin. Neurobiol Aging. 1990 Mar-Apr;11(2):123–129. doi: 10.1016/0197-4580(90)90045-2. [DOI] [PubMed] [Google Scholar]
  3. Benowitz L. I., Rodriguez W., Paskevich P., Mufson E. J., Schenk D., Neve R. L. The amyloid precursor protein is concentrated in neuronal lysosomes in normal and Alzheimer disease subjects. Exp Neurol. 1989 Dec;106(3):237–250. doi: 10.1016/0014-4886(89)90156-8. [DOI] [PubMed] [Google Scholar]
  4. Brion J. P., Couck A. M., Passareiro E., Flament-Durand J. Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study. J Submicrosc Cytol. 1985 Jan;17(1):89–96. [PubMed] [Google Scholar]
  5. Burger P. C., Vogel F. S. The development of the pathologic changes of Alzheimer's disease and senile dementia in patients with Down's syndrome. Am J Pathol. 1973 Nov;73(2):457–476. [PMC free article] [PubMed] [Google Scholar]
  6. Castaño E. M., Frangione B. Human amyloidosis, Alzheimer disease and related disorders. Lab Invest. 1988 Feb;58(2):122–132. [PubMed] [Google Scholar]
  7. Coyle J. T., Oster-Granite M. L., Reeves R. H., Gearhart J. D. Down syndrome, Alzheimer's disease and the trisomy 16 mouse. Trends Neurosci. 1988 Sep;11(9):390–394. doi: 10.1016/0166-2236(88)90075-6. [DOI] [PubMed] [Google Scholar]
  8. Davies L., Wolska B., Hilbich C., Multhaup G., Martins R., Simms G., Beyreuther K., Masters C. L. A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology. 1988 Nov;38(11):1688–1693. doi: 10.1212/wnl.38.11.1688. [DOI] [PubMed] [Google Scholar]
  9. Delabar J. M., Goldgaber D., Lamour Y., Nicole A., Huret J. L., de Grouchy J., Brown P., Gajdusek D. C., Sinet P. M. Beta amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome. Science. 1987 Mar 13;235(4794):1390–1392. doi: 10.1126/science.2950593. [DOI] [PubMed] [Google Scholar]
  10. Gearhart J. D., Davisson M. T., Oster-Granite M. L. Autosomal aneuploidy in mice: generation and developmental consequences. Brain Res Bull. 1986 Jun;16(6):789–801. doi: 10.1016/0361-9230(86)90075-4. [DOI] [PubMed] [Google Scholar]
  11. Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
  12. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., Gajdusek D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. doi: 10.1126/science.3810169. [DOI] [PubMed] [Google Scholar]
  13. Gropp A., Kolbus U., Giers D. Systematic approach to the study of trisomy in the mouse. II. Cytogenet Cell Genet. 1975;14(1):42–62. doi: 10.1159/000130318. [DOI] [PubMed] [Google Scholar]
  14. Grundke-Iqbal I., Iqbal K., George L., Tung Y. C., Kim K. S., Wisniewski H. M. Amyloid protein and neurofibrillary tangles coexist in the same neuron in Alzheimer disease. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2853–2857. doi: 10.1073/pnas.86.8.2853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heston L. L., Mastri A. R., Anderson V. E., White J. Dementia of the Alzheimer type. Clinical genetics, natural history, and associated conditions. Arch Gen Psychiatry. 1981 Oct;38(10):1085–1090. doi: 10.1001/archpsyc.1981.01780350019001. [DOI] [PubMed] [Google Scholar]
  16. KIDD M. ALZHEIMER'S DISEASE--AN ELECTRON MICROSCOPICAL STUDY. Brain. 1964 Jun;87:307–320. doi: 10.1093/brain/87.2.307. [DOI] [PubMed] [Google Scholar]
  17. KIDD M. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature. 1963 Jan 12;197:192–193. doi: 10.1038/197192b0. [DOI] [PubMed] [Google Scholar]
  18. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
  19. Kosik K. S., Joachim C. L., Selkoe D. J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044–4048. doi: 10.1073/pnas.83.11.4044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Levy E., Carman M. D., Fernandez-Madrid I. J., Power M. D., Lieberburg I., van Duinen S. G., Bots G. T., Luyendijk W., Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124–1126. doi: 10.1126/science.2111584. [DOI] [PubMed] [Google Scholar]
  21. Lovett M., Goldgaber D., Ashley P., Cox D. R., Gajdusek D. C., Epstein C. J. The mouse homolog of the human amyloid beta protein (AD-AP) gene is located on the distal end of mouse chromosome 16: further extension of the homology between human chromosome 21 and mouse chromosome 16. Biochem Biophys Res Commun. 1987 Apr 29;144(2):1069–1075. doi: 10.1016/s0006-291x(87)80073-6. [DOI] [PubMed] [Google Scholar]
  22. Masters C. L., Multhaup G., Simms G., Pottgiesser J., Martins R. N., Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 1985 Nov;4(11):2757–2763. doi: 10.1002/j.1460-2075.1985.tb04000.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mori H., Kondo J., Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science. 1987 Mar 27;235(4796):1641–1644. doi: 10.1126/science.3029875. [DOI] [PubMed] [Google Scholar]
  25. Oliver C., Holland A. J. Down's syndrome and Alzheimer's disease: a review. Psychol Med. 1986 May;16(2):307–322. doi: 10.1017/s0033291700009120. [DOI] [PubMed] [Google Scholar]
  26. Perry G., Mulvihill P., Manetto V., Autilio-Gambetti L., Gambetti P. Immunocytochemical properties of Alzheimer straight filaments. J Neurosci. 1987 Nov;7(11):3736–3738. doi: 10.1523/JNEUROSCI.07-11-03736.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Price D. L., Whitehouse P. J., Struble R. G., Coyle J. T., Clark A. W., Delong M. R., Cork L. C., Hedreen J. C. Alzheimer's disease and Down's syndrome. Ann N Y Acad Sci. 1982;396:145–164. doi: 10.1111/j.1749-6632.1982.tb26850.x. [DOI] [PubMed] [Google Scholar]
  28. Reeves R. H., Robakis N. K., Oster-Granite M. L., Wisniewski H. M., Coyle J. T., Gearhart J. D. Genetic linkage in the mouse of genes involved in Down syndrome and Alzheimer's disease in man. Brain Res. 1987 Sep;388(3):215–221. doi: 10.1016/0169-328x(87)90028-3. [DOI] [PubMed] [Google Scholar]
  29. Robakis N. K., Wisniewski H. M., Jenkins E. C., Devine-Gage E. A., Houck G. E., Yao X. L., Ramakrishna N., Wolfe G., Silverman W. P., Brown W. T. Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome. Lancet. 1987 Feb 14;1(8529):384–385. doi: 10.1016/s0140-6736(87)91754-5. [DOI] [PubMed] [Google Scholar]
  30. Roher A., Wolfe D., Palutke M., KuKuruga D. Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2662–2666. doi: 10.1073/pnas.83.8.2662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rumble B., Retallack R., Hilbich C., Simms G., Multhaup G., Martins R., Hockey A., Montgomery P., Beyreuther K., Masters C. L. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989 Jun 1;320(22):1446–1452. doi: 10.1056/NEJM198906013202203. [DOI] [PubMed] [Google Scholar]
  32. Selkoe D. J., Abraham C. R., Podlisny M. B., Duffy L. K. Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease. J Neurochem. 1986 Jun;46(6):1820–1834. doi: 10.1111/j.1471-4159.1986.tb08501.x. [DOI] [PubMed] [Google Scholar]
  33. TERRY R. D. THE FINE STRUCTURE OF NEUROFIBRILLARY TANGLES IN ALZHEIMER'S DISEASE. J Neuropathol Exp Neurol. 1963 Oct;22:629–642. doi: 10.1097/00005072-196310000-00005. [DOI] [PubMed] [Google Scholar]
  34. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. doi: 10.1126/science.2949367. [DOI] [PubMed] [Google Scholar]
  35. Terry R. D., Katzman R. Senile dementia of the Alzheimer type. Ann Neurol. 1983 Nov;14(5):497–506. doi: 10.1002/ana.410140502. [DOI] [PubMed] [Google Scholar]
  36. Van Broeckhoven C., Genthe A. M., Vandenberghe A., Horsthemke B., Backhovens H., Raeymaekers P., Van Hul W., Wehnert A., Gheuens J., Cras P. Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families. Nature. 1987 Sep 10;329(6135):153–155. doi: 10.1038/329153a0. [DOI] [PubMed] [Google Scholar]
  37. Van Broeckhoven C., Haan J., Bakker E., Hardy J. A., Van Hul W., Wehnert A., Vegter-Van der Vlis M., Roos R. A. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science. 1990 Jun 1;248(4959):1120–1122. doi: 10.1126/science.1971458. [DOI] [PubMed] [Google Scholar]
  38. Wischik C. M., Novak M., Thøgersen H. C., Edwards P. C., Runswick M. J., Jakes R., Walker J. E., Milstein C., Roth M., Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4506–4510. doi: 10.1073/pnas.85.12.4506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wiśniewski H. M., Narang H. K., Terry R. D. Neurofibrillary tangles of paired helical filaments. J Neurol Sci. 1976 Feb;27(2):173–181. doi: 10.1016/0022-510x(76)90059-9. [DOI] [PubMed] [Google Scholar]
  40. Wong C. W., Quaranta V., Glenner G. G. Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8729–8732. doi: 10.1073/pnas.82.24.8729. [DOI] [PMC free article] [PubMed] [Google Scholar]

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