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Interaction of the Presenilins with the Amyloid Precursor Protein (APP)

  • Andreas Weidemann
  • Krzysztof Paliga
  • Ulrike Dürrwang
  • Friedrich Reinhard
  • Dai Zhang
  • Rupert Sandbrink
  • Geneviève Evin
  • Colin L. Masters
  • Konrad Beyreuther
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 32)

Abstract

The genes encoding presenilin-1 (PS1) and presenilin-2 (PS2) were identified as the genes that harbour mutations that cause more than 60% of early onset familial Alzheimer’s disease cases (FAD) (1-3). So far, more than 40 missense mutations have been described for presenilin-1 and two have been found in the gene coding for presenilin-2 (reviewed in refs. 4 and 5). Carriers of mutated presenilin genes develop in their brain neuropathological changes characteristic of Alzheimer’s disease including the deposition of amyloid Aβ peptide. The latter is released from its cognate amyloid precursor protein (APP) by a two-step proteolytic conversion: first, proteolysis of APP by β-secretase, which releases the N-terminus of Aβ, and second, conversion of the remaining fragment by γ-secretase, which cleaves within the predicted transmembrane region of APP. This releases the C-terminus of Aβ, which may end either at position 40 or, to a lesser extent, at position 42 (reviewed in ref. 6). The latter species, Aβ1-42, is more prone to aggregation and deposition than Aβ1-40 and is produced at higher levels in the brains and primary fibroblasts of FAD patients carrying PS missense mutations (7). The same result was obtained when cultured cells transfected with mutated PS1 orPS2, or transgenic mice harboring missense PS1 were analyzed for the production of Aβ1-42: in every case increased amounts of the longer Aβ1-42 species were observed (8-10). The mechanisms by which mutations in the PS genes affect the proteolytic processing of APP by γ-secretase have not been resolved in detail. There are two possibilities by which the normal processing of APP may be disturbed: either mutations in the presenilins affect APP metabolism in an indirect way by modulation of proteases or interaction with proteins involved in APP intracellular routing, or presenilins may modulate APP processing directly through physical interactions with APP. Such a direct interaction between presenilins and APP was first demonstrated by us for PS2 (11). Later on, formation of stable complexes with APP was reported not only for PS2 but also for PS1 (12,13,13a).

Keywords

Amyloid Precursor Protein Amyloid Precursor Protein Processing Amyloid Precursor Protein Expression Intermediate Compartment Calcium Phosphate Coprecipitation 
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.

References

  1. 1.
    Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.CrossRefPubMedGoogle Scholar
  2. 2.
    Levy-Lahad, E., Wasco, W., Pookaj, P., Romano, D., Oshima, J., Pettingell, P., et al. (1995) Candidate Gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.CrossRefPubMedGoogle Scholar
  3. 3.
    Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., et al. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778.CrossRefPubMedGoogle Scholar
  4. 4.
    Tanzi, R. E., Kovacs, D. M., Kim, T. W., Moir, R. D., Guenette, S. Y., and Wasco, W. (1996) The gene defects responsible for familial Alzheimer’s disease. Neurobiol. Dis. 3, 159–168.CrossRefPubMedGoogle Scholar
  5. 5.
    Mattson, M. P., Guo, Q., Furukawa, K., and Pedersen, W. A. (1998) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer’s disease. J. Neurochem. 70, 1–14.CrossRefPubMedGoogle Scholar
  6. 6.
    Selkoe, D. J. (1997) Alzheimer’s disease: genotypes, phenotypes, and treatments. Science 275, 630–631.CrossRefPubMedGoogle Scholar
  7. 7.
    Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., et al. (1996) Secreted amyloid β-protein similar to that in the senile plaque of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med. 2, 864–870.CrossRefPubMedGoogle Scholar
  8. 8.
    Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez tur, J., et al. (1996) Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.CrossRefPubMedGoogle Scholar
  9. 9.
    Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013.CrossRefPubMedGoogle Scholar
  10. 10.
    Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer’s disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43) residue. Proc. Natl. Acad. Sci. USA 94, 2025–2030.CrossRefPubMedGoogle Scholar
  11. 11.
    Weidemann, A., Paliga, K., Dürrwang, U., Czech, C., Evin, G., Masters, C. L., and Beyreuther, K. (1997) Formation of stable complexes between two Alzheimer’s disease gene products: presenilin-2 and β-amyloid precursor protein. Nat. Med. 3, 328–332.CrossRefPubMedGoogle Scholar
  12. 12.
    Xia, W., Zhang, J., Perez, R., Koo, E. H., and Selkoe, D. J. (1997) Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 8208–8213.CrossRefPubMedGoogle Scholar
  13. 13.
    Wasco, W., Tanzi, R. E., Moir, R. D., Crowley, A. C., Merriam, D. E., Romano, D. M., et al. (1998) Presenilin 2-APP interactions, in Presenilins and Alzheimer’s Disease (Younkin, S. G., Tanzi, R. E., and Christen, Y., eds.), Springer, Heidelberg, Germany, pp. 59–70.Google Scholar
  14. 13a.
    Pradier, L., Carpentier, N., Delalonde, L., Clavel, N., Bock, M. D., Buee, L., Mercken, L., Tocque, B., and Czech, C. (1999) Mapping the APP/presenilin (PS) binding domains: the hydrophilic N-terminus of PS2 is sufficient for interaction with APP and can displace APP/PS1 interaction. Neurobiol. Dis. 6, 43–55.CrossRefPubMedGoogle Scholar
  15. 14.
    Thinakaran, G., Borchelt, D. R., Lee, M. K., Slunt, H. H., Spitzer, L., Kim, G., et al. (1996) Endoproteolysis of presenilin 1 and acumulation of processed derivatives in vivo. Neuron 17, 181–190.CrossRefPubMedGoogle Scholar
  16. 15.
    Kovacs, D. M., Fausett, H. J., Page, K. J., Kim, T. W., Moir, R. D., Merriam, D. E., et al. (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat. Med. 2, 224–229.CrossRefPubMedGoogle Scholar
  17. 16.
    Cook, D. B., Sung, J. C., Golde, T. E., Felsenstein, K. M., Wojczyk, B. S., Tanzi, R. E., et al. (1996) Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites. Proc. Natl. Acad. Sci. USA 93, 9223–9228.CrossRefPubMedGoogle Scholar
  18. 17.
    Culvenor, J. G., Maher, F., Evin, G., Malchiodi-Albedi, F., Cappai, R., Underwood, J. R., et al. (1997) Alzheimer’s disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment. J. Neurosci. Res. 49, 719–731.CrossRefPubMedGoogle Scholar
  19. 18.
    De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–90.CrossRefPubMedGoogle Scholar
  20. 19.
    Qian, S., Jiang, P., Guan, X. M., Singh, G., Trumbauer, M. E., Yu, H., et al. (1998) Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression. Neuron 20, 611–617.CrossRefPubMedGoogle Scholar
  21. 20.
    Davis, J. A., Naruse, S., Chen, H., Eckman, C., Younkin, S., Price, D. L., et al. (1998) An Alzheimer’s disease-linked PS1 variant rescues the developmental abnormalities of PS 1-deficient embryos. Neuron 20, 603–609.CrossRefPubMedGoogle Scholar
  22. 21.
    Hammond, C. and Helenius, A. (1994) Quality control. in the secretory pathway: retention of misfolded viral membrane glycoprotein involves cycling between the ER, intermediate compartment, and Golgi apparatus. J. Cell Biol. 126, 41–52.CrossRefPubMedGoogle Scholar
  23. 22.
    Nichols, W. C., Seligsohn, U., Zivelin, A., Terry, V. H., Hertel, C. E., Wheatley, M. A., et al. (1998) Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 93, 61–70.CrossRefPubMedGoogle Scholar
  24. 23.
    Weidemann, A., König, G., Bunke, D., Fischer, P., Salbaum, J. M., Masters, C. L., and Beyreuther, K. (1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57, 115–126.CrossRefPubMedGoogle Scholar
  25. 24.
    Schöler, H. R. and Gruss, P. (1984) Specific interaction between enhancer-containing molecules and cellular components. Cell 36, 403–411.CrossRefPubMedGoogle Scholar
  26. 25.
    Kunkel, T. A., Roberts, J. D., and Zakour, R. A. (1987) Rapid and efficient site specific mutagenesis without phenotypic selection. Methods Enzymol. 154, 367–382.CrossRefPubMedGoogle Scholar
  27. 26.
    Dyrks, T., Dyrks, E., Mönning, U., Urmoneit, B., Turner, J., and Beyreuther, K. (1993) Generation of βA4 from the amyloid protein precursor and fragments thereof. FEBS Lett. 335, 89–93.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2000

Authors and Affiliations

  • Andreas Weidemann
    • 1
  • Krzysztof Paliga
    • 1
  • Ulrike Dürrwang
    • 1
  • Friedrich Reinhard
    • 1
  • Dai Zhang
    • 1
  • Rupert Sandbrink
    • 1
  • Geneviève Evin
    • 2
  • Colin L. Masters
    • 2
  • Konrad Beyreuther
    • 1
  1. 1.Zentrum fur Molekulare Biologie HeidelbergHeidelbergGermany
  2. 2.Department of PathologyUniversity of MelbourneParkvilleAustralia

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