DOI QR코드

DOI QR Code

Control of Morphology and Subsequent Toxicity of AβAmyloid Fibrils through the Dequalinium-induced Seed Modification

  • Kim, Jin-A (School of Chemical and Biological Engineering, College of Engineering, Seoul National University) ;
  • Myung, Eun-Kyung (School of Chemical and Biological Engineering, College of Engineering, Seoul National University) ;
  • Lee, In-Hwan (School of Chemical and Biological Engineering, College of Engineering, Seoul National University) ;
  • Paik, Seung-R. (School of Chemical and Biological Engineering, College of Engineering, Seoul National University)
  • Published : 2007.12.20

Abstract

Amyloid fibril formation of amyloid β/A4 protein (Aβ) is critical to understand the pathological mechanism of Alzheimer's disease and develop controlling strategy toward the neurodegenerative disease. For this purpose, dequalinium (DQ) has been employed as a specific modifier for Aβ aggregation and its subsequent cytotoxicity. In the presence of DQ, the final thioflavin-T binding fluorescence of Aβ aggregates decreased significantly. It was the altered morphology of Aβ aggregates in a form of the bundles of the fibrils, distinctive from normal single-stranded amyloid fibrils, and the resulting reduced β-sheet content that were responsible for the decreased fluorescence. The morphological transition of Aβ aggregates assessed with atomic force microscope indicated that the bundle structure observed with DQ appeared to be resulted from the initial multimeric seed structure rather than lateral association of preformed single-stranded fibrils. Investigation of the seeding effect of the DQ-induced Aβ aggregates clearly demonstrated that the seed structure has determined the final morphology of Aβ aggregates as well as the aggregative kinetics by shortening the lag phase. In addition, the cytotoxicity was also varied depending on the final morphology of the aggregates. Taken together, DQ has been considered to be a useful chemical probe to control the cytotoxicity of the amyloid fibrils by influencing the seed structures which turned out to be central to develop therapeutic strategy by inducing the amyloid fibrils in different shapes with varied toxicities.

Keywords

References

  1. Coyle, J. T.; Price, D. L.; DeLong, M. R. Science 1983, 219(4589), 1184 https://doi.org/10.1126/science.6338589
  2. Bourin, M.; Ripoll, N.; Dailly, E. Curr. Med. Res. Opin. 2003, 19, 169 https://doi.org/10.1185/030079903125001631
  3. Tanzi, R.; Bertram, L. Cell 2005, 120(4), 545 https://doi.org/10.1016/j.cell.2005.02.008
  4. Jarrett, J. T.; Berger, E. P.; Lansbury, P. T. Jr. Biochemistry 1993, 32(18), 4693 https://doi.org/10.1021/bi00069a001
  5. Selkoe, D. J. Nature 1999, 399, A23 https://doi.org/10.1038/19866
  6. Younkim, S. G. Ann. Neurol. 1995, 37, 287 https://doi.org/10.1002/ana.410370303
  7. Hardy, J. A.; Selkoe, D. J. Science 2002, 297(5580), 353 https://doi.org/10.1126/science.1072994
  8. Yang, D. S.; Yip, C. M.; Huang, T. H.; Chakrabartty, A.; Fraser, P. E. J. Biol. Chem. 1999, 274(46), 32970 https://doi.org/10.1074/jbc.274.46.32970
  9. Williams, A. D.; Sega, M.; Chen, M.; Kheterpal, I.; Geva, M.; Berthelier, V.; Kaleta, D. T.; Cook, K. D.; Wetzel, R. Proc. Natl. Acad. Sci. USA 2005, 102(20), 7115 https://doi.org/10.1073/pnas.0408582102
  10. Necula, M.; Kayed, R.; Milton, S.; Glabe, C. G. J. Biol. Chem. 2007, 282(14), 10311 https://doi.org/10.1074/jbc.M608207200
  11. Diamant, S.; Podoly, E.; Friedler, A.; Ligumsky, H.; Livnah, O.; Soreq, H. Proc. Natl. Acad. Sci. USA 2006, 103(23), 8628 https://doi.org/10.1073/pnas.0602922103
  12. Marambaud, P.; Zhao, H.; Davies, P. J. Biol. Chem. 2005, 280(45), 37377 https://doi.org/10.1074/jbc.M508246200
  13. Lee, C.-H.; Kim, H. J.; Lee, J.-H.; Cho, H.-J.; Kim, J.; Chung, K. C.; Jung, S.; Paik, S. R. J. Biol. Chem. 2006, 281(6), 3463 https://doi.org/10.1074/jbc.M505307200
  14. Weiss, M. J.; Wong, J. R.; Ha, C. S.; Bleday, R.; Salem, R. R.; Steele, G. D.; Chen, L. B. Proc. Natl. Acad. Sci. USA 1987, 84, 5444 https://doi.org/10.1073/pnas.84.15.5444
  15. Zhuo, S.; Allison, W. S. Biochem. Biophys. Res. Commun. 1988, 152, 968 https://doi.org/10.1016/S0006-291X(88)80378-4
  16. Zhuo, S.; Paik, S. R.; Register, J. A.; Allison, W. S. Biochemistry 1993, 32, 2219 https://doi.org/10.1021/bi00060a013
  17. Rotenberg, S. A.; Smiley, S.; Ueffing, M.; Krauss, R. S.; Chen, L. B.; Weinstein, I. B. Cancer Res. 1990, 50, 677
  18. Sullivan, R. M.; Stone, M.; Marshall, J. F.; Uberall, F.; Rotenberg, S. A. Mol. Pharmacol. 2000, 58, 729 https://doi.org/10.1124/mol.58.4.729
  19. Petkova, A. T.; Leapman, R. D.; Guo, Z.; Yau, W. M.; Mattson, M. P.; Tycko, R. Science 2005, 307(5707), 262 https://doi.org/10.1126/science.1105850
  20. Bergamaschini, L.; Rossi, E.; Storini, C.; Pizzimenti, S.; Distaso, M.; Perego, C.; De Luigi, A.; Vergani, C.; Grazia De Simoni, M. J. Neurosci. 2004, 24, 4181 https://doi.org/10.1523/JNEUROSCI.0550-04.2004
  21. Ashur-Fabian, O.; Segal-Ruder, Y.; Skutelsky, E.; Brenneman, D. E.; Steingart, R.; Giladi, E.; Gozes, I. Peptides 2003, 24, 1413 https://doi.org/10.1016/j.peptides.2003.08.005
  22. Ono, S.; Mohri, K.; Ono, K. J. Biol. Chem. 2004, 279(14), 14207 https://doi.org/10.1074/jbc.M313418200
  23. Koh, C. J.; Lee, M. Bull. Korean Chem. Soc. 2006, 27(4), 477 https://doi.org/10.5012/bkcs.2006.27.4.477
  24. Kang, D.-I.; Baek, D.; Shin, S. Y.; Kim, Y. Bull. Korean Chem. Soc. 2005, 26(8), 1225 https://doi.org/10.5012/bkcs.2005.26.8.1225

Cited by

  1. Shear-induced structure and mechanics of β-lactoglobulin amyloid fibrils vol.5, pp.24, 2009, https://doi.org/10.1039/b914089a
  2. Chemometric Studies on Brain-uptake of PET Agents via VolSurf Analysis vol.29, pp.1, 2007, https://doi.org/10.5012/bkcs.2008.29.1.061