YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Effects of 3-Phenyl-1-isoquinolinamine on the Metabolism of ${\beta}$-Amyloid Precursor Protein in Neuroblastoma Cells

3-페닐-1-이소퀴놀린아민이 신경세포에서 베타 아밀로이드 전구단백질의 대사에 미치는 영향

  • Leem, Jae-Yoon (College of Pharmacy, Woosuk University) ;
  • Cho, Won-Jea (College of Pharmacy and Research Institute of Drug Development, Chonnam National University)
  • Received : 2010.11.26
  • Accepted : 2010.12.03
  • Published : 2010.12.31
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Abstract

Alzheimer's disease (AD) is characterized pathologically by the presence of intracellular neurofibrillary tangles and deposition of ${\beta}$-amyloid ($A{\beta}$) peptides, which are generated by processing of amyloid precursor protein (APP). It is urgent to develop effective therapies for the treatment of AD, since our society rapidly accelerate aging. $A{\beta}$ peptides have been believed to be neurotoxic and now are also considered to have effects on the mechanism of memory formation. Recently, we investigated that a quinoline compound from natural product reduced the secretion of $A{\beta}$ from the neuroblastoma N2a cells (NL/N cell line) overexpressing APPswe. In this study, 3-phenyl-1-isoquinolinamine, a synthetic isoquinoline compound was analyzed to determine its effects on the metabolism of APP. It inhibited the secretion of $A{\beta}$ peptides from the N2a NL/N cell line. Beta-site APP cleaving enzyme (BACE) fluorescence resonance energy transfer (FRET) assay revealed that it inhibited BACE activity in a dose dependent manner. Immunoblotting study showed that it inhibited APP stabilization and expression and it slightly increased the stablization and the expression of ${\gamma}$-secreatase component from the N2a NL/N cell line. We suggest that 3-phenyl-1-isoquinolinamine inhibits APP metabolism and $A{\beta}$ generation by the means of BACE inhibitory mechanism. This is the first report that 3-phenyl-1-isoquinolinamine inhibits the secretion of $A{\beta}$ peptides from neuroblastoma cells.

Keywords

References

  1. Bertram, L., Lill, C. M. and Tanzi, R. E. : The genetics of Alzheimer disease: back to the future. Neuron. 68, 270 (2010). https://doi.org/10.1016/j.neuron.2010.10.013
  2. Sugimoto, H. : Donepezil hydrochloride: a treatment drug for Alzheimer's disease. Chem. Rec. 1, 63 (2001). https://doi.org/10.1002/1528-0691(2001)1:1<63::AID-TCR9>3.0.CO;2-J
  3. Zarotsky, V., Sramek, J. J., and Cutler, N. R. : Galantamine hydrobromide: an agent for Alzheimer's disease. Am. J. Health Syst. Pharm. 60, 446 (2003).
  4. Jann, M. W. : Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy 20, 1 (2000). https://doi.org/10.1592/phco.20.1.1.34664
  5. Iqbal, K., Sisodia, S. S. and Winblad, B. : Alzheimer's disease: Advances in etionlogy, pathogenesis and therapeutics. John Wiley & Sons, Ltd. (2001).
  6. Morris, J. C. : Classification of dementia and Alzheimer's disease. Acta Neurol. Scand. 165, 41 (1996).
  7. Braak, H., Braak, E. and Strothjohann, M. : Abnormally phosphorylated tau protein related to the formation of neurofibrillary tangles and neuropil threads in the cerebral cortex of sheep and goat. Neurosci Lett. 171, 1 (1994). https://doi.org/10.1016/0304-3940(94)90589-4
  8. Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K. and Muller-Hill, B. : The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733 (1987). https://doi.org/10.1038/325733a0
  9. Selkoe, D. J. : The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 8, 447 (1998). https://doi.org/10.1016/S0962-8924(98)01363-4
  10. Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. and Roses, A. D. : Binding of human apolipoprotein E to synthetic amyloid beta peptide isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 8098 (1993). https://doi.org/10.1073/pnas.90.17.8098
  11. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L. and Pericak-Vance, M. A. : Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921 (1993). https://doi.org/10.1126/science.8346443
  12. Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M. A., Biere, A. L., Curran, E., Burgess, T., Louis, J. C., Collins, F., Treanor, J., Rogers, G. and Citron, M. : $\beta$-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735 (1999). https://doi.org/10.1126/science.286.5440.735
  13. Selkoe, D. J. : Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, 23 (1999). https://doi.org/10.1038/19866
  14. Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., Song, Y. Q., Rogaeva, E., Chen, F., Kawarai, T., Supala, A., Levesque, L., Yu, H., Yang, D. S., Holmes, E., Milman, P., Liang, Y., Zhang, D. M., Xu, D. H., Sato, C., Rogaev, E., Smith, M., Janus, C., Zhang, Y., Aebersold, R., Farrer, L. S., Sorbi, S., Bruni, A., Fraser, P. and St. George-Hyslop, P. : Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and ${\beta}APP $ processing. Nature 407, 48 (2000). https://doi.org/10.1038/35024009
  15. Lee, S. F., Shah, S., Li, H., Yu, C., Han, W. and Yu, G. : Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-$\beta$ precursor protein and Notch. J. Biol. Chem. 277, 45013 (2002). https://doi.org/10.1074/jbc.M208164200
  16. Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M. and Haass, C. : PEN-2 is an integral component of the $\gamma$-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem. 277, 39062 (2002). https://doi.org/10.1074/jbc.C200469200
  17. Hardy, J. and Selkoe, D. J. : The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353 (2002). https://doi.org/10.1126/science.1072994
  18. Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D. R., Price, D. L. and Wong, P. C. : BACE1 is the major -secretase for generation of A peptides by neurons. Nature Neurosci. 4, 233 (2001). https://doi.org/10.1038/85064
  19. Leem, J. Y., et al. : Effect of a quinoline compound from the oriental medicine on the metabolism of $\beta$-amyloid precursor protein in neuroblastoma cells. (manuscript in preparation).
  20. Cho, W. J., Min, S. Y., Le, T. N. and Kim, T. S. : Synthesis of new 3-arylisoquinolinamines: effect on topoisomerase I inhibition and cytotoxicity. Bioorg. Med. Chem. Lett. 13, 4451 (2003). https://doi.org/10.1016/j.bmcl.2003.09.001
  21. Wang, R., Sweeney, D., Gandy, S. E. and Sissodia, S. S. : The profile of soluble amyloid $\beta$ protein in cultured cell media. J. Biol. Chem. 271, 31894 (1996). https://doi.org/10.1074/jbc.271.50.31894
  22. Tung, J. S., Davis, D. L., Anderson, J. P., Walker, D. E., Mamo, S., Jewett, N., Hom, R. K., Sinha, S., Thorsett, E. D. and John, V. : Design of substrate-based inhibitors of human $\beta$-secretase. J. Med. Chem. 45, 259 (2002). https://doi.org/10.1021/jm0155695
  23. Kinoshita, A., Fukumoto, H., Shah, T., Whelan, C. M., Irizarry, M. C. and Hyman, B. T. : Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J. Cell. Sci. 116, 3339 (2003). https://doi.org/10.1242/jcs.00643
  24. Leem, J. Y., Saura, C. A., Pietrzik, C., Christianson, J., Wanamaker, C., King, L. T., Veselits, M. L., Tomita, T., Gasparini, L., Iwatsubo, T., Xu, H., Green, W. N., Koo, E. H. and Thinakaran, G. : A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface. Neurobiol. Dis. 11, 64 (2002). https://doi.org/10.1006/nbdi.2002.0546
  25. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I. Rommens, J., Kim, S., Schenk, D., Fraser, P., St George Hyslop, P. and Selkoe. D. J. : Mutant presenilins of Alzheimer's disease increase production of 42- residue amyloid $\beta$-protein in both transfected cells and transgenic mice, Nat. Med. 3, 67 (1997). https://doi.org/10.1038/nm0197-67
  26. Kuo, Y. M., Emmerling, M. R., Vigo-Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G. H., Ball, M. J. and Roher, A. E. : Water-soluble $A{\beta}$ (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 271, 4077 (1996). https://doi.org/10.1074/jbc.271.8.4077
  27. Takahashi, Y., Hayashi, I., Tominari, Y., Rikimaru, K., Morohashi, Y., Kan, T., Natsugari, H., Fukuyama, T., Tomita, T. and Iwatsubo, T. : Sulindac sulfide is a noncompetitive $\gamma$-secretase inhibitor that preferentially reduces $A{\beta}$ 42 generation. J. Biol. Chem. 278, 18664 (2003). https://doi.org/10.1074/jbc.M301619200
  28. Sambamurti, K., Hardy, J., Refolo L. M. and Lahiri, D. K. : Targeting APP metabolism for the treatment of Alzheimer's disease. Drug Dev. Res. 56, 211 (2002). https://doi.org/10.1002/ddr.10077
  29. Skovronsky, D. M., Moore, D. B., Milla, M. E., Doms, R. W. and Lee, V. M. : Protein kinase C-dependent $\alpha$-secretase competes with $\beta$-secretase for cleavage of amyloid-$\beta$ precursor protein in the trans-golgi network. J. Biol. Chem. 275, 2568 (2000). https://doi.org/10.1074/jbc.275.4.2568
  30. Nunan, J. and Small, D. H. : Regulation of APP cleavage by ${\alpha}-,\;{\beta}-\;and\;{\gamma}$-secretases. FEBS Lett. 483, 6 (2000). https://doi.org/10.1016/S0014-5793(00)02076-7
  31. Kulkarni, S. K. and Dhir, A. : Berberine, a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res. 24, 317 (2010). https://doi.org/10.1002/ptr.2968
  32. Jung, H. A., Min, B. S., Yokozawa, T., Lee, J. H., Kim, Y. S. and Choi, J. S. : Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol. Pharm. Bull. 32, 1433 (2009). https://doi.org/10.1248/bpb.32.1433