Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Aβ deposition inhibitor screen using synthetic amyloid

Nature Biotechnology volume 15, pages 258–263 (1997)Cite this article

Abstract

The formation, growth, and maturation of brain amyloid “senile” plaques are essential pathological processes in Alzheimer's disease (AD) and key targets for therapeutic intervention. The process of in vitro deposition of Aβ at physiological concentrations onto plaques in AD brain preparations has been well characterized, but is cumbersome for drug discovery. We describe here a high-throughput screen for inhibitors of Aβ deposition onto a synthetic template (synthaloid) of fibrillar Aβ immobilized in a polymer matrix. Synthaloid is indistinguishable from plaques in AD brain (the natural template) in deposition kinetics, pH profile, and structure-activity relationships for both Aβ analogs and inhibitors. Synthaloid, in contrast to current Aβ aggregation screens, accurately predicted inhibitor potency for Aβ deposition onto AD cortex preparations, validating its use in searching for agents that can slow the progression of AD and exposing a previously inaccessible target for drug discovery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Hardy, J. and Allsop, D. 1991. Amyloid deposition as the central event in the etiology of Alzheimer's disease. Trends Pharmacol. Sci. 12: 383–388.

    Article  CAS  Google Scholar 

  2. Selkoe, D.J. 1994. Alzheimer's disease: a central role for amyloid. J. Neuropathol. Exp. Neurol. 53: 438–447.

    Article  CAS  Google Scholar 

  3. Vinters, H.V., Wang, Z.Z., and Secor, D.L. 1996. Brain parenchymal and microvascular amyloid in Alzheimer's disease. Brain. Pathol. 6: 179–195.

    Article  CAS  Google Scholar 

  4. Schenk, D.B., Russell, R.E., May, P., Little, S., Panetta, J., Lieberburg, I. et al. 1995. Therapeutic approaches related to amyloid-β peptide and Alzheimer's disease. J. Medic. Chem. 38: 4141–4154.

    Article  CAS  Google Scholar 

  5. Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C. et al. 1995. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523–527.

    Article  CAS  Google Scholar 

  6. LaFerla, P.M., Tinkle, B.T., Bieberich, C.J., Haudenschild, C.C., and Jay, G., 1995. Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genetics 9: 21–29.

    Article  CAS  Google Scholar 

  7. Cummings, B.J. and Cotman, C.W. 1995. Image analysis of β-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet 326: 1524–15287.

    Article  Google Scholar 

  8. Schellenberg, G.D. 1995. Genetic dissection of Alzheimer's disease, a heterogeneous disorder. Proc. Natl. Acad. Sci. USA 92: 8552–8559.

    Article  CAS  Google Scholar 

  9. Selkoe, D.J. 1996. Amyloid β-protein and the genetics of Alzheimer's disease. J. Biol. Chem. 271: 18295–18298.

    Article  CAS  Google Scholar 

  10. 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 plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Medicine 2: 864–870.

    Article  CAS  Google Scholar 

  11. Seubert, P., Vigo-Pelfrey, C., Esch, R., Lee, M., Dovey, H., Davis, D. et al. 1992. Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids. Nature 359: 325–327.

    Article  CAS  Google Scholar 

  12. Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfre, C., Mellon, A., Ostaszewski, B.L. et al. 1992. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359: 322–325.

    Article  CAS  Google Scholar 

  13. Kirschner, D.A., Inouye, H., Duffy, L.K., Sinclair, A., Lind, M., and Selkoe, D.J. 1987. Synthetic peptide homologous to β protein from Alzheimer's disease forms amyloid-like fibrils in vitro. Proc. Natl. Acad. Sci. USA 84: 6953–6957.

    Article  CAS  Google Scholar 

  14. Jarrett, J.T. and Lansbury, P.T. 1993. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73: 1055–1058.

    Article  CAS  Google Scholar 

  15. Zheng, H., Jiang, M., Trumbauer, M.E., Siriinathsinghji, D.J., Hopkins, R., Smith, D.W. et al. 1995. Beta-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomoter activity. Cell 81: 525–553.

    Article  CAS  Google Scholar 

  16. Tomiyama, T., Shoji, A., Kataoka, K., Suwa, Y., Asano, S., Kaneko, H., and Endo, N. 1996. Inhibition of amyloid β-protein aggregation and neurotoxicity by rifampicin. J. Biol. Chem. 271: 6839–6844.

    Article  CAS  Google Scholar 

  17. Wood, S.J., MacKenzie, L., Maleeff, B., Hurle, M.R., and Wetzel, R. 1996. Selective inhibition of Aβ fibril formation. J. Biol. Chem. 271: 4086–4092.

    Article  CAS  Google Scholar 

  18. Pollack, S.J., Sadlere, I.I.J., Hawtin, S.R., Tailor, V.J., and Shearman, M.S. 1995. Sulfonated dyes attenuate the toxic effects of β-amyloid in a structure specific fashion. Neurosci. Lett. 197: 211–214.

    Article  CAS  Google Scholar 

  19. Soto, C., Kindy, M.S., Baumann, M., and Frangione, B. 1996. Inhibition of Alzheimer's amyloidosis by peptides that prevent β-sheet conformation. Biochem. Biophys. Res. Com. 226: 672–680.

    Article  CAS  Google Scholar 

  20. Tjernberg, L.O., Naslund, J., Lindqvist, F., Johansson, J., Karlstrom, A.R., Thyberg, J. et al. 1996. Arrest of beta-amyloid fibril formation by a pentapeptide ligand. J. Biochem. 271: 8545–8548.

    CAS  Google Scholar 

  21. Maggio, J.E. and Mantyh, R.W. 1996. Brain amyloid—a physiochemical perspective. Brain. Pathol. 6: 147–162.

    Article  CAS  Google Scholar 

  22. Lomakin, A., Chung, D.S., Benedek, G.B., Kirschner, D.A., and Teplow, D.B. 1996. On the nucleation and growth of amyloid β-protein fibrils. Proc. Nat. Acad. Sci. USA 93: 1125–1129.

    Article  CAS  Google Scholar 

  23. Esler, W.P., Stimson, E.R., Ghilardi, J.R., Vinters, H.V., Lee, J.R., Mantyh, P.W. et al. 1996. In vitro growth of Alzheimer's disease β-amyloid plaques displays first-order kinetics. Biochemistry 35: 749–757.

    Article  CAS  Google Scholar 

  24. Naiki, H. and Nakakuki, K. 1996. First-order kinetic model of Alzheimer's β-amyloid fibril extension in vitro. Lab. Invest. 74: 374–383.

    CAS  PubMed  Google Scholar 

  25. Mantyh, P.W., Stimson, E.R., Ghilardi, J.R., Alien, C.J., Dahl, C.E., Whitcomb, D.C. et al. 1991. Reversible in vitro growth of Alzheimer disease β-amyloid plaques. Bull. Clin. Neurosci. 56: 73–85.

    Google Scholar 

  26. Maggio, J.E., Stimson, E.R., Ghilardi, J.R., Alien, C.J., Dahl, C.E., Whitcomb, D.C. et al. 1992. Reversible in vitro growth of Alzheimer disease β-amyloid plaques by deposition of labeled amyloid peptide. Proc. Natl. Acad. Sci. USA 89: 5462–5466.

    Article  CAS  Google Scholar 

  27. Lee, J.R., Stimson, E.R., Ghilardi, J.R., Mantyh, P.W., Lum, Y.-A., Felix, A.M. et al. 1995. 1H NMR of Aβ amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence. Biochemistry 34: 5191–5200.

    Article  CAS  Google Scholar 

  28. Esler, W.P., Stimson, E.R., Ghilardi, J.R., Lu, Y.-A., Felix, A.M., Vinters, H.V. et al. 1996. Point substitution in the central hydrophobic cluster of a human β-amyloid congener disrupts peptide folding and abolishes plaque competence. Biochemistry 44: 13914–13921.

    Article  Google Scholar 

  29. Weldon, D.T., Cleary, D.P., Esler, W.P., Ghilardi, J.R., O'Hare, E., Rogers, S.D. et al. 1996. Neurotoxicity of Aβ peptide: confocal imaging of cellular changes induced by β-amyloid in rat CNS in vivo. Soc. Neurosci. Abs. 22: 475.

    Google Scholar 

  30. Evans, K.C., Berger, E.P., Cho, C.-G., Weisgraber, K.H., and Lansbury, P.T. 1995. Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: Implications for the pathogenesis and treatment of Alzheimer disease. Proc. Natl. Acad. Sci. USA. 92: 763–767.

    Article  CAS  Google Scholar 

  31. Kelly, J.W. 1996. Alternative conformations of amyloidogenic proteins govern their behavior. Curr. Opin. Struct. Biol. 6: 11–17.

    Article  CAS  Google Scholar 

  32. Hyman, B.T., West, H.L., Rebek, G.W., Buldyrev, S.V., Mantegna, R.N., Ukleja, M. et al. 1995. Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc. Nat. Acad. Sci. USA 92: 3586–3590.

    Article  CAS  Google Scholar 

  33. Ghilardi, J.R., Catton, M., Stimson, E.R., Rogers, S., Walker, L.C., Maggio, J.E. et al. 1996. Intra-arterial infusion of 125l-Aβ1–40 labels amyloid deposits in the aged primate brain in vivo. NeuroReport 7: 2607–2511.

    Article  CAS  Google Scholar 

  34. Fraser, P.E., Nguyen, J.T., Inouye, H., Surewicz, W.K., Selkoe, D.J., Podlisny, M.B. et al. 1992. Fibril formation by rodent, Dutch-Hemorrhagic analogs of Alzheimer β-protein. Biochemistry 31: 10716–10723.

    Article  CAS  Google Scholar 

  35. Esler, W.P., Stimson, E.R., Jennings, J.J., Ghilardi, J.R., Mantyh, P.W., and Maggio, J.E. 1996. Zinc-induced aggregation of human and rat β-amyloid peptides in vitro. J. Neurochem. 66: 723–732.

    Article  CAS  Google Scholar 

  36. Mantyh, P.W., Ghilardi, J.R., Rogers, S., DeMaster, E., Alien, C.J., Stimson, E.R. et al. 1993. Aluminum, iron and zinc ions promote aggregation of physiological concentrations of β-amyloid peptide. J. Neurochem. 61: 1171–1174.

    Article  CAS  Google Scholar 

  37. Podlisny, M.B., Ostazewski, B.L., Sqazzo, S.L., Koo, E.H., Rydell, R.E., Teplow, D.B. et al. 1995. Aggregation of secreted amyloid β-protein into sodium dodecyl sulfate-stable oligomers in cell culture. J. Biol. Chem. 270: 9564–9570.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. John E. Maggio: Corresponding author (e-mail: maggio@bcmp.med.harvard.edu).

Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA, 02115

    William P. Esler & Evelyn R. Stimson

  2. Molecular Neurobiology Research (151), VA Medical Center and Department of Psychiatry, University of Minnesota, Minneapolis, MN, 55417

    Joseph R. Ghilardi & Patrick W. Mantyh

  3. Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN, 37232

    Yi-An Lu

  4. Department of Chemistry and Physics, William Paterson College, Wayne, NJ, 07470

    Arthur M. Felix

  5. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095

    Harry V. Vinters

Authors
  1. William P. Esler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Evelyn R. Stimson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joseph R. Ghilardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arthur M. Felix
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-An Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Harry V. Vinters
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patrick W. Mantyh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John E. Maggio
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Esler, W., Stimson, E., Ghilardi, J. et al. Aβ deposition inhibitor screen using synthetic amyloid. Nat Biotechnol 15, 258–263 (1997). https://doi.org/10.1038/nbt0397-258

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt0397-258

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing