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Transgenic Rat and In-Vitro Studies of β-Amyloid Precursor Protein Processing

  • Kevin M. Felsenstein
  • Allison Treloar
  • Janet M. Roome
  • Lisa W. Hunihan
  • Kim M. Ingalls
  • Susan B. Roberts
Part of the Advances in Behavioral Biology book series (ABBI, volume 44)

Abstract

The brains of individuals afflicted with Alzheimer’s Disease (AD) are characterized pathologically by cortical atrophy, deposition of senile plaques (i.e. ß-amyloid protein), and the formation of neurofibrillary tangles. The etiology of AD is complex and multifactorial; including evidence for genetic heterogeneity. However, genetic studies have clearly shown that several different mutations in the ß-APP gene on chromosome 21 are unambiguously pathogenic for AD in a subset of early-onset families.1–9 The mechanism by which ß-protein is generated and formed into amyloid in-vivo have yet to be defined. Aside from the genetic data, putative pathological mechanisms may include overexpression of ß-APP, as suggested by trisomy 21 or Down’s Syndrome individuals; or alterations in the proteolytic processing pathways, currently being defined in-vitro by a number of laboratories. To date no animal model exists that can recapitulate the pathological cascade of AD.

Keywords

Amyloid Precursor Protein Mock Transfected Cell Alzheimer Amyloid Precursor Protein Carboxy Terminal Region Human Placental Alkaline Phosphatase 
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.

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References

  1. 1.
    E. Levy, M.D. Carman, I. Fernandez-Madrid, M.D. Power, I. Lieberburg, S.G. Van Duinen, G.T.A.M. Bots, W. Luyenkijk, and B. Frangione, Mutation of the Alzheimer’s disPAce amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science 248: 1124–1126 (1990).PubMedCrossRefGoogle Scholar
  2. 2.
    P. H. St. George-Hyslop, The genetic defect causing familial Alzheimer’s disease maps on chromosome 21, Science 235: 885–890 (1987).CrossRefGoogle Scholar
  3. 3.
    A. Goate, M.-C. Chartier-Harlin, M. Mullan, J. Brown, F. Crawford, L. Fidani, L. Giuffra, A. Haynes, N. Irving, L. James, R. Mant, P. Newton, K. Rooke, P. Roques, C. Talbot, M. Pericak-Vance, A. Roses, R. Williamson, M. Rossen, M. Owen, and J. Hardy, Segregation of a missense mutation in the amyloid precursor protein with familial Alzheimer’s disease, Nature 349: 704–706 (1991).PubMedCrossRefGoogle Scholar
  4. 4.
    J. Hardy, M. Mullan, M.-C Chartier-Harlin, J. Brown, A. Goate, M. Rossor, J. Collinge, G. Roberts, P. Luthert, P. Lantos, S. Naruse, K. Kaneko, S. Tsuji, T. Miyatake, T. Shimizu, T. Kojima, I. Nakano, K. Yoshioka, Y. Sakaki, T. Miki, T. Katsuya, T. Ogihara, A. Roses, M. Pericak-Vance, J. Haan, R. Roos, G. Lucotte, and F. Favid, Molecular classification of Alzheimer’s disease, Lancet 337: 1342–1343 (1991).Google Scholar
  5. 5.
    S. Naruse, S. Igarashi, H. Kobayashi, K. Aoka, T. Inuzuka, K. Kaneko, T. Shimizu, K. Idhara, T. Kojima, T. Miyatake, and S. Tsuji, Mis-sense mutation ValIle in exon 17 of amyloid precursor protein in Japanese familial Alzheimer’s disease, Lancet 337: 978–979 (1991).PubMedCrossRefGoogle Scholar
  6. 6.
    C.M. Van Duijn, L. Hendriks, M. Cruts, J.A. Hardy, A. Hofman, and C. Van Broeckhoven, Amyloid precursor protein gene mutation in early-onset Alzheimer’s disease, Lancet 337: 978 (1991).PubMedCrossRefGoogle Scholar
  7. 7.
    J. Murrell, M. Farlow, B. Ghetti, and M.D. Benson. A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease, Science 254: 97–99 (1991).PubMedCrossRefGoogle Scholar
  8. 8.
    M-C. Chartier-Harlin, F. Crawford, H. Houlden, A. Warren, D. Hughes, L.Fidani, A. Goate, M. Rossor, P. Roques, J. Hardy, and M. Mullan, Early-onset Alzheimer’s disease caused by mutations at codon 717 of the B-amyloid precursor protein gene, Nature 353: 844–846 (1991).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Mullan, F. Crawford, K. Axelman, H. Houlden, L. Lilius, B. Winblad, and L. Lannfelt, A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of ß-amyloid, Nature Genet. 1:345–347 (1992).Google Scholar
  10. 10.
    S.S. Sisodia and D.L. Price, Amyloidogenesis in Alzheimer’s disease• basic biology and animal models, Curr. Opin. Neurobiol. 2: 648–652 (1992).PubMedCrossRefGoogle Scholar
  11. 11.
    D. Quon, Y. Wang, R. Catalino, J.M. Scardina, K. Murakami, and B. Cordell, Formation of ß-amyloid protein deposits in brains of transgenic mice, Nature 352: 239–241 (1991).PubMedCrossRefGoogle Scholar
  12. 12.
    S. Kawabata, G.A. Higgins, and J.W. Gordon, Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein, Nature 354:476–478 (1991); Retracted Nature 356: 23 (1992).PubMedCrossRefGoogle Scholar
  13. 13.
    A. Kammesheidt, F.M. Boyce, A.F. Spanoyannis, B.J. Cummings, M. Ortegon, C. Cotman, J.L. Vaught, and R.L. Neve, Deposition of B/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl terminal fragment of the Alzheimer amyloid precursor in the brain, Proc. Natl. Acad. Sci. USA 89: 10857–10861 (1992).PubMedCrossRefGoogle Scholar
  14. 14.
    M. Jucker, L.C. Walker, L.J. Martin, C.A. Kitt, H.K. Kleinman, D.K. Ingram, and D.L. Price, Age-associated inclusions in normal and transgenic mouse brain, Science 255: 1443–1445 (1992).PubMedCrossRefGoogle Scholar
  15. 15.
    B.T. Lamb, S.S. Sisodia, A.M. Lawler, H.H. Slunt, C.A. Kitt, W.G. Kearns, P.L. Pearson, D.L. Price, and J.D. Gearhart, Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice, Nature Genetics 5: 22–30 (1993)PubMedCrossRefGoogle Scholar
  16. 16.
    J. Berger, J. Hauber, R. Hauber, R. Geiger, and B.R. Cullen, Secreted placental alkaline phosphatase: a powerful new quantitative indicator of gene expression in eukaryotic cells, Gene 66: 1–10 (1988).PubMedCrossRefGoogle Scholar
  17. 17.
    P. Henthorn, P.Zervos, M. Raducha, H. Harris, and T. Kadesch, Expression of a human placental alkaline phosphatase gene in transfected cells: Use as a reporter for studies of gene expression, Proc. Natl. Acad. Sci. USA 85: 6342–6346 (1988).PubMedCrossRefGoogle Scholar
  18. 18.
    A. Weidemann, G. Konig, D. Bunke, P. Fischer, J.M. Salbaum, C.L. Masters, and K. Beyreuther, Identification, biogenesis and localization of precursors of Alzheimer’s disease A4 amyloid protein, J. Biol. Chem. 266: 16960–16964 (1989).Google Scholar
  19. 19.
    J.P. Anderson, L.M. Refolo, W. Wallace, P. Mehta, M. Krishnamurthi, J. Gotlib, L. Bierer, V. Haroutunian, D. Perl, and N.K. Robakis, Differential brain expression of the Alzheimer amyloid precursor protein, EMBO J. 8: 3627–3632 (1989).PubMedGoogle Scholar
  20. 20.
    J.P. Anderson, Y. Chen, K.S. Kim and N.K. Robakis. An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a. potentially amyloidogenic sequence, Neurochem. J. 59: 2328–2331 (1992).Google Scholar
  21. 21.
    S.S. Sisodia, Amyloid precursor protein cleavage by a membrane bound protease, Proc. Natl. Acad. Sci. USA 89: 6075–6079 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    T.E. Golde, S. Estus, L. Younkin, D.J. Selkoe and S.G. Younkin, Processing of the amyloid protein precursor to potentially amyloidogenic derivatives, Science 255: 728–730 (1992).PubMedCrossRefGoogle Scholar
  23. 23.
    S.R. Sahasrabudhe, M.A. Spruyt, H.A. Muenkel, A.J. Blume, M.P. Vitek, and J.S. Jacobsen, Release of amino-terminal fragments from amyloid precursor protein reporter and mutated derivatives in cultured cells, J. Biol. Chem. 267: 25602–25608 (1992).PubMedGoogle Scholar
  24. 24.
    S. Sisodia, E.H. Koo, K. Beyreuther, A. Unterbeck, and D.L. Price, Evidence that ß-amyloid protein in Alzheimer’s disease is not derived by normal processing, Science 248: 492–495 (1990).PubMedCrossRefGoogle Scholar
  25. 25.
    C.Haass, M.G. Schlossmacher, A.Y. Hung, C. Vigo-Pelfrey, A. Mellon, B.L. Ostaszewski, I. Lieberburg, E.H. Koo, D. Schenk, D.B. Teplow, and D.J. Selkoe, Targeting of cell surface B amyloid precursor to lysosomes: Alternative processing in amyloid bearing fragments, Nature 357: 500–503 (1992).CrossRefGoogle Scholar
  26. 26.
    K. Felsenstein and L. Lewis-Higgins, Processing of the B-amyloid precursor protein carrying the familial, Dutch-type, and a novel recombinant C-terminal mutation, Neurosci. Letts. 152: 185–189 (1993).CrossRefGoogle Scholar
  27. 27.
    M. Citron, T. Oltersdorf, C. Haass, L. McConlogue, A.Y. Hung, P. Seubert, C. Vigo-Pelfrey, I. Lieberburg, and D.J. Selkoe, Mutation of the B-amyloid precursor protein in familial Alzheimer’s disease increase B-protein production. Nature 360: 672–674 (1992).PubMedCrossRefGoogle Scholar
  28. 28.
    X-D. Cai, T.E. Golde, and S.G. Younkin, Release of excess amyloid B protein from a mutant amyloid B protein precursor, Science 259: 514–516 (1993).PubMedCrossRefGoogle Scholar
  29. 29.
    J.R. Sayers, W. Schmidt, and F. Eckstein, 5’-3’ exonuclease in phosphorothioate-based olignucleotide directed mutagenesis, Nucleic Acids Res. 16: 791–802 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    G.L. Caporaso, S.E. Gandy, J.D. Buxbaum, and P. Greengard, Chloroquine inhibits intracellular degradation but not secretion of Alheimer ß/A4 amyloid precursor protein, Proc. Natl. Acad. Sci. USA 89: 2252–2256 (1992)PubMedCrossRefGoogle Scholar
  31. 31.
    R.M. Nitsch, B.E. Slack, R.J. Wurtman, and J.H. Growdon, Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors, Science 258: 304–307, (1992).PubMedCrossRefGoogle Scholar
  32. 32.
    B.F. Hogan, F. Constantin, and E. Lacy, Manipulating the mouse embryo. A laboratory manual, Cold Spring Harbor Laboratory Press (1986).Google Scholar
  33. 33.
    G.G. Gleaner and C.W. Wong, Alzheimer’s disease and Down’s Syndrome: Sharing of a unique cerebrovascular amyloid fibril protein, Biochem. Biophys. Res. Commun. 122: 1131–1135 (1984b).CrossRefGoogle Scholar
  34. 34.
    C.L. Masters, G. Multhaup, G. Simms, J. Pottgiesser, R.N. Martins, and K. Beyreuther, Neuronal origin of a cerebral amyloid: Neurofibrillary tangles of Alzheimer’s dise9sP contain the same protein as the amyloid of plaque cores and blood vessels, EMBO J. 4: 2757–2763 (1985).PubMedGoogle Scholar
  35. 35.
    G.G. Glenner and C.W. Wong, Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem. Biophys. Res. Commun. 120: 9855–890 (1984a).CrossRefGoogle Scholar
  36. 36.
    J. Kang, H.-G. Lemaire, A. Unterbeck, J.M. Salbaum, C.L. Masters, K.-H. Grzeschik, G. Multhaup, K. Beyreuther, B. Muller-Hill, The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell surface receptor, Nature 325: 733–736 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Kevin M. Felsenstein
    • 1
  • Allison Treloar
    • 1
  • Janet M. Roome
    • 1
  • Lisa W. Hunihan
    • 1
  • Kim M. Ingalls
    • 1
  • Susan B. Roberts
    • 1
  1. 1.Bristol-Myers Squibb Pharmaceutical Research InstituteCNS-Drug DiscoveryWallingfordUSA

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