Journal of Molecular Neuroscience

, Volume 19, Issue 1–2, pp 51–55 | Cite as

Per-6-substituted β-cyclodextrin libraries inhibit formation of β-amyloid-peptide (Aβ)-derived, soluble oligomers

  • Jiaxin Yu
  • Lara Bakhos
  • Lei Chang
  • Mark J. Holterman
  • William L. Klein
  • Duane L. Venton
Lead Compound Discovery And Optimization

Abstract

Alzheimer’s disease is the most common cause of dementia in older individuals with compelling evidence favoring neuron dysfunction and death triggered by assembled forms of Aβ1–42. While large neurotoxic amyloid fibrils have been known for years, recent studies show that soluble protofibril and Aβ1–42-derived diffusible ligands (ADDLs) may also be involved in neurotoxicity. In the present work, dot-blot immunoassays discriminating ADDLs from monomers were used to screen libraries of per-substituted β-cyclodextrin (β-CD) derivatives for inhibition of ADDLs formation. Libraries were prepared from per-6-iodo-β-CD by treatment with various amine nucleophiles. The most active library tested (containing >2000 derivatives) was derived from imidazole, N, N-dimethylethylenediamine and furfurylamine, which at 10 µM total library, inhibited ADDLs formation (10 nM1–42) over a period of 4 hours. The latter was confirmed by a western blot assay showing decreased amounts of the initially formed Aβ1–42 tetramer. These preliminary experiments suggest that derivatized forms of β-CD can interfere with the oligomerization process of Aβ1–42.

Index Entries

Alzheimer’s beta amyloid ADDLs beta cyclodextrin combinatorial chemistry 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ashton P. R., Koniger R., Stoddart J. F., Alker D., and Harding V. D. (1996) Amino acid derivatives of beta-cyclodextrin. J. Org. Chem. 61, 903–908.CrossRefGoogle Scholar
  2. Camilleri P., Haskins J. J., and Howlett D. R. (1994) beta-Cyclodextrin interacts with the Alzheimer amyloid beta-A4 peptide. Fed. Euro. Biochem. Soc. Lett. 341, 256–258.Google Scholar
  3. Drouet B., Pincon-Raymond M., and Chambaz J, Pillot T. (1999) Laminin 1 attenuates beta-amyloid peptide Abeta (1–40) neurotoxicity of cultured fetal rat cortical neurons. J. Neurochem. 73, 742–749.PubMedCrossRefGoogle Scholar
  4. Givol D. (1974) Affinity labeling and topology of the antibody combining site. Essays Biochem. 10, 73–103.PubMedGoogle Scholar
  5. Golde T. E., Eckman C. B., and Younkin S. G. (2000) Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer’s disease. J. Biochem. Biophys. Acta 1502, 172–187.Google Scholar
  6. Hartley D. M., Walsh D. M., Ye C. P., Diehl T., Vasquez S., Vassilev P. M., et al. (1999) Profibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19, 8876–8884.PubMedGoogle Scholar
  7. Howlett D., Cutler P., Heales S., and Camilleri P. (1997) Hemin and related porphyrins inhibit beta-amyloid aggregation. Fed. Euro. Biochem. Soc. Lett. 417, 249–251.Google Scholar
  8. Howlett D. R., Perry A. E., Godfrey F., Swatton J. E., Jennings K. H., Spitzfaden C., et al. (1999) Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans. Biochem. J. 340, 283–289.PubMedCrossRefGoogle Scholar
  9. Hsia A. Y., Masliah E., McConlogue I., Yu G. Q., Tatsuno G., Hu K., et al. (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233.PubMedCrossRefGoogle Scholar
  10. Klein W. L. (2001) Fibrils, Protofibrils & Abeta-Derived Diffusible Ligands: How Abeta Causes Neuron Dysfunction and Death in Alzheimer’s Disease. Humana Press, Totowa, NJ.Google Scholar
  11. Lambert M. P., Barlow A. K., Chromy B. A., Edwards C., Freed R., Liosatos M., et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448–6453.PubMedCrossRefGoogle Scholar
  12. Lambert M. P., Viola K. L., Cromy B. A., Chang L., Morgan T. E., Yu J., et al. (2001) Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J. Neurochem., 79, 595–605.PubMedCrossRefGoogle Scholar
  13. Longo V. D., Viola K. L., Klein W. L., and Finch C. E. (2000) Reversible inactivation of superoxide-sensitive aconitase in Abeta1-42-treated neuronal cell lines. J. Neurochem. 75, 12243–12247.CrossRefGoogle Scholar
  14. Lorenzo A. and Yankner B. A. (1994) Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc. Natl. Acad. Sci. USA 91, 12243–12247.PubMedCrossRefGoogle Scholar
  15. Mucke L., Masliah E., Yu G. Q., Mallory M., Rockenstein E. M., Tatsuno G., et al. (2000) High-level neuronal expression of Abeta 1–42 in wild-type human amy-loid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058.PubMedGoogle Scholar
  16. Pappolla M., Bozner P., Soto C., Shao H., Robakis N. K., Zagorski M., Frangione B., and Ghiso J. (1998) Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J. Biol. Chem. 273, 7185–7188.PubMedCrossRefGoogle Scholar
  17. Pike C. J., Burdick D., Walencewicz A. J., Glabe C. G., Cotman C. W. (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13, 1676–1687.PubMedGoogle Scholar
  18. Schubert D. (1997) Serpins inhibit the toxicity of amyloid peptides. Eur. J. Neurosci. 9, 770–777.PubMedCrossRefGoogle Scholar
  19. Small D.H. (1998) The amyloid cascade hypothesis debate: emerging consensus on the role of Abeta and amyloid in Alzheimer’s disease. The Sixth International Conference on Alzheimer’s disease, Amsterdam, The Netherlands, pp. 301–304.Google Scholar
  20. Solomon B., Koppel R., Frankel D., and Hanan-Aharon E. (1997) Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc. Natl. Acad. Sci. USA 94, 4109–4112.PubMedCrossRefGoogle Scholar
  21. Solomon B., Koppel R., Hanan E., and Katzav T. (1996) Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc. Natl. Acad. Sci. USA 93, 452–455.PubMedCrossRefGoogle Scholar
  22. Soto C., Kindy M. S., Baumann M., and Frangione B. (1996) Inhibition of Alzheimer’s amyloidosis by peptides that prevent beta-sheet conformation. Biochem. Biophys. Res. Comm. 226, 672–680.PubMedCrossRefGoogle Scholar
  23. Soto C., Sigurdsson E. M., Morelli L., Kumar R. A., Castano E. M., and Frangione B. (1998) Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy [see comments]. Nature Med. 4, 822–826.PubMedCrossRefGoogle Scholar
  24. Tomiyama T., Asano S., Suwa Y., Morita T., Kataoka K., Mori H., and Endo N. (1994) Rifampicin prevents the aggregation and neurotoxicity of amyloid beta protein in vitro. Biochem. Biophys. Res. Commun. 204, 76–83.PubMedCrossRefGoogle Scholar
  25. Tomiyama T., Shoji A., Kataoka K., Suwa Y., Asano S., Kaneko H., and Endo N. (1996) Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J. Biol. Chem. 271, 6839–6844.PubMedCrossRefGoogle Scholar
  26. Waite J., Cole G. M., Frautschy S. A., Connor D. J., and Thal L. J. (1992) Solvent effects on beta protein toxicity in vivo. Neurobiol. Aging 13, 595–599.PubMedCrossRefGoogle Scholar
  27. Walsh D. M., Hartley D. M., Kusumoto Y., Fezoui Y., Condron M. M., Lomakin A., et al. (1999) Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274, 25945–25952.PubMedCrossRefGoogle Scholar
  28. Walsh D. M., Lomakin A., Benedek G. B., Condron M. M., and Teplow D. B. (1997) Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J. Biol. Chem. 272, 22364–22372.PubMedCrossRefGoogle Scholar
  29. Wood S. J., MacKenzie L., Maleff B., Hurle M. R., and Wetzel R. (1996) Selective inhibition of Abeta fibril formation. J. Biol. Chem. 271, 4086–4092.PubMedCrossRefGoogle Scholar
  30. Yu G. S., Hu J., and Nakagawa H. (1998) Inhibition of beta-amyloid cytotoxicity by midkine. Neurosci. Lett. 254, 125–128.PubMedCrossRefGoogle Scholar
  31. Yu J., Zhao Y., Holterman M. J., and Venton D. L. (1999) Combinatorial search of substituted beta-cyclodextrins for phosphatase-like activity. Bioorg. Med. Chem. Lett. 9, 2705–2710.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Jiaxin Yu
    • 1
  • Lara Bakhos
    • 3
  • Lei Chang
    • 3
  • Mark J. Holterman
    • 2
  • William L. Klein
    • 3
  • Duane L. Venton
    • 1
  1. 1.Department of Medicinal Chemistry and Pharmacognosy, College of PharmacyThe University of Illinois at ChicagoChicago
  2. 2.Department of Surgery, College of MedicineThe University of Illinois at ChicagoChicago
  3. 3.Department of Neurobiology and PhysiologyNorthwestern UniversityEvanston

Personalised recommendations