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The metabolism of the amyloid precursor protein and its relevance to Alzheimer's disease

  • Perspectives Part I. Eucaryotic Host Proteases
  • Published:
Perspectives in Drug Discovery and Design

Summary

The pathology of Alzheimer's disease is primarily characterized by the deposition of β-amyloid/Aβ peptide as the major component of senile or neuritic plaques. The Aβ peptide is produced as a result of proteolytic cleavage of the transmembrane protein precursor, APP, during its normal cellular metabolism. The free amino terminus of the Aβ peptide is generated by an endopeptidic cleavage between Met671-Asp672 by a protease termed β-secretase. Increased cleavage at this site takes place in a rare, inherited double mutation (Lys670-Met671 to Asn670-Leu671), leading to increased Aβ production and consequent development of Alzheimer's disease on an accelerated time scale in the affected individuals, underscoring the pathological importance of β-secretase activity. Cellular studies provide direct evidence that inhibition of β-secretase activity would appear to be effective in inhibiting Aβ production as a rational approach to developing therapeutics for the disease.

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References

  1. Selkoe, D.J., Podlisny, M.B., Joachim, C.L., Vickers, E.A., Lee, G., Fritz, L.C. and Oltersdorf, T., Proc. Natl. Acad. Sci. USA, 85 (1988) 7341.

    Google Scholar 

  2. Glenner, G.G. and Wong, C.W., Biochem. Biophys. Res. Commun., 120 (1984) 885.

    PubMed  Google Scholar 

  3. Masters, C.L., Simms, G., Weinman, N.A., Multhaup, G., McDonald, B.L. and Beyreuther, K., Proc. Natl. Acad. Sci. USA, 82 (1985) 4245.

    Google Scholar 

  4. Abraham, C.R., Selkoe, D.J. and Potter, H., Cell, 52 (1988) 487.

    Google Scholar 

  5. Kang, J., Lemaire, H.G., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K.H., Multhaup, G., Beyreuthre, K. and Muller-Hill, B., Nature, 325 (1987) 733.

    PubMed  Google Scholar 

  6. Ponte, P., Gonzalez-DeWhitt, P., Schilling, J., Miller, J., Hsu, D., Greenberg, B., Davis, K., Wallace, W., Lieberburg, I. and Fuller, F., Nature, 331 (1988) 525.

    PubMed  Google Scholar 

  7. Tanzi, R.E., McClatchey, A.I., Lamperti, E.D., Villa-Komaroff, L., Gusella, J.F. and Neve, R.L., Nature, 331 (1988) 528.

    PubMed  Google Scholar 

  8. Kitaguchi, N., Takahasi, Y., Tokushima, Y., Shiojiri, S. and Ito, H., Nature, 331 (1988) 530.

    PubMed  Google Scholar 

  9. De Sauvage, F. and Octave, J.-N., Science, 245 (1989) 651.

    Google Scholar 

  10. Konig, G., Mönning, U., Czech, C., Prior, R., Banati, R., Schreiter-Gassre, U., Bauer, J., Masters, C.L. and Beyreuther, K., J. Biol. Chem., 267 (1992) 10804.

    Google Scholar 

  11. Sandbrink, R., Masters, C.L. and Beyreuther, K., J. Biol. Chem., 269 (1994) 1510.

    Google Scholar 

  12. Weidemann, A., Konig, G., Bunke, D., Fischer, P., Salbaum, J.M., Masters, C.L. and Beyreuther, K., Cell, 57 (1989) 115.

    Google Scholar 

  13. Oltersdorf, T., Fritz, L.C., Schenk, D.B., Lieberburg, I., Johnson-Wood, K.L., Beattie, E.C., Ward, P.J., Blacher, R.W., Dovey, H.F. and Sinha, S., Nature, 341 (1989) 144.

    Google Scholar 

  14. Kuentzel, S.L., Ali, S.M., Ahman, R.D., Greenberg, B.D. and Raub, T.J., Biochem. J., 295 (1993) 367.

    Google Scholar 

  15. Esch, F.S., Keim, P.S., Beattie, E.C., Blacher, R.W., Culwell, A.R., Oltersdorf, T., McClure, D. and Ward, P.J., Science, 248 (1990) 1122.

    PubMed  Google Scholar 

  16. Knops, J., Lieberburg, I. and Sinha, S., J. Biol. Chem., 267 (1992) 16022.

    Google Scholar 

  17. Estus, S., Golde, T.E., Kunishita, T., Blades, D., Lowery, D., Eisen, M., Usiak, M., Qu, X.M., Tabira, T., Greenberg, B.D. and Younkin, S.G., Science, 255 (1992) 726.

    Google Scholar 

  18. Golde, T.E., Estus, S., Younkin, L.H., Selkoe, D.J. and Younkin, S.G., Science, 255 (1992) 728.

    PubMed  Google Scholar 

  19. Haass, C., Koo, E.H., Mellon, A. and Hung, A.Y., Nature, 357 (1992) 500.

    Google Scholar 

  20. Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schlossmacher, M., Whaley, J., Swindlehurst, C., McCormack, R., Wolfert, R., Lieberburg, I. and Schenk, D., Nature, 359 (1992) 325.

    Google Scholar 

  21. Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B.L., Lieberburg, I., Koo, E.H., Schenk, D., Teplow, D.B. and Selkoe, D.J., Nature, 359 (1992) 322.

    PubMed  Google Scholar 

  22. Shoji, M., Golde, T.E., Ghiso, J., Cheung, T.T., Estus, S., Shaffer, L.N., Cai, X.D., McKay, D.M., Tintner, R., Frangione, B. and Younkin, S.G., Science, 258 (1992) 126.

    PubMed  Google Scholar 

  23. Vigo-Pelfrey, C., Lee, D., Keim, P., Lieberburg, I. and Schenk, D.B., J. Neurochem., 61 (1993) 1965.

    Google Scholar 

  24. Haass, C., Hung, A.Y., Schlossmacher, M.G., Teplow, D.B. and Selkoe, D.J., J. Biol. Chem., 268 (1993) 3021.

    Google Scholar 

  25. Seubert, P., Oltersdorf, T., Lee, M.G., Barbour, R., Blomquist, C., Davis, D.L., Bryant, K., Fritz, L.C., Galasko, D., Thal, L.J., Lieberburg, I. and Schenk, D.B., Nature, 361 (1993) 260.

    PubMed  Google Scholar 

  26. Goate, A., Chartier-Harlin, M.-C., 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. and Hady, J., Nature, 349 (1991) 704.

    PubMed  Google Scholar 

  27. Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B. and Lannfelt, K., Nat. Genet., 1 (1992) 345.

    Google Scholar 

  28. Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A.Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I. and Selkoe, D.J., Nature, 360 (1992) 672.

    Google Scholar 

  29. Cai, X.-D., Golde, T.E. and Younkin, S.G., Science, 259 (1993) 514.

    Google Scholar 

  30. Dovey, H.F., Suomensaari-Chrysler, S., Lieberburg, I., Sinha, S. and Keim, P., NeuroReport, 4 (1993) 1039.

    Google Scholar 

  31. Knops, J., Suomensaari, S., Lee, M., McConlogue, L., Seubert, P. and Sinha, S., J. Biol. Chem., 270 (1995) 2419.

    Google Scholar 

  32. Cai, X.-D., Cheung, T.T. and Younkin, S.G., Soc. Neurosci. Abstr., 19 (1993) 431.

    Google Scholar 

  33. Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee, M., Leibowitz, 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., Sorlano, F., Tan, H., Vitale, J., Wadsworth, S., Wolozin, B. and Zhao, J., Nature, 373 (1995) 523.

    Google Scholar 

  34. Caporaso, G.L., Gandy, S.E., Buxbaum, J.D., Ramabhadran, T.V. and Greenard, P., Proc. Natl. Acad. Sci. USA, 89 (1992) 3055.

    Google Scholar 

  35. Nitsch, R.M., Slack, B.E., Farbre, S.A., Barghesani, P.R., Schulz, J.G., Kim, C., Felder, C.C., Crowdon, J.H. and Wurtman, R.J., Ann. New York Acad. Sci., 695 (1993) 122.

    Google Scholar 

  36. Buxbaum, J.D., Koo, E.H. and Greengard, P., Proc. Natl. Acad. Sci. USA, 90 (1993) 9195.

    Google Scholar 

  37. Gabuzda, D., Busciglio, J. and Yankner, B.D., J. Neurochem., 61 (1993) 2326.

    Google Scholar 

  38. Strittmater, W.J., Saunders, A.M., Schenechel, D., Pericak-Vance, M., Enghild, J., Slavesen, G.S. and Roses, A.D., Proc. Natl. Acad. Sci. USA, 90 (1993) 1977.

    Google Scholar 

  39. Saunders, A.H., Schmoder, K., Brutner, J.C.S., Benson, M.D., Brown, W.T., Goldfarb, L., Goldgaber, D., Manwaring, M.G., Szymanski, M.H., McCrown, N., Dole, K.C., Schmechel, D.E., Strittmatter, W.J., Pericak-Vance, M.A. and Roses, A.D., Neurology, 43 (1993) 1467.

    Google Scholar 

  40. Rebeck, G.W., Reiter, J.S., Strickland, D.K. and Hyman, B.T., Neuron, 11 (1993) 575.

    Google Scholar 

  41. Strittmatter, W.J., Weisgraber, K.H., Goedert, M., Saunders, A.M., Huang, D., Corder, E.H., Dong, L.M., Jakes, R., Alberts, M.J. and Gilbert, J.R., Exp. Neurol., 125 (1994) 163.

    Google Scholar 

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  1. Athena Neurosciences, 800-F, Gateway Boulevard, 94080, South San Francisco, CA, U.S.A.

    Sukanto Sinha

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Sinha, S. The metabolism of the amyloid precursor protein and its relevance to Alzheimer's disease. Perspectives in Drug Discovery and Design 2, 363–369 (1995). https://doi.org/10.1007/BF02172030

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  • DOI: https://doi.org/10.1007/BF02172030

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