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. 1996 Mar 1;314(Pt 2):701–707. doi: 10.1042/bj3140701

The conformation of Alzheimer's beta peptide determines the rate of amyloid formation and its resistance to proteolysis.

C Soto 1, E M Castaño 1
PMCID: PMC1217103  PMID: 8670088

Abstract

Amyloid beta-peptide (A beta) is found in an aggregated poorly soluble form in senile or neuritic plaques deposited in the brain of individuals affected by Alzheimer's disease (AD). In addition soluble A beta (sA beta) is identified normally circulating in human body fluids. In this study we report that synthetic peptides containing the sequences 1-40 and 1-42 of A beta, and A beta analogues bearing amino acid substitutions can adopt two major conformational states in solution: (1) an amyloidogenic conformer (A beta ac) with a high content of beta-sheet and partly resistant to proteases and (2) a non-amyloidogenic conformer (A beta nac) with a random coil conformation and protease-sensitive. The differences in the fibrillogenesis rate and in the protease resistance among the several A beta peptides studied depend mainly on the relative propensity for adopting the amyloidogenic conformation, which in the absence of external factors is largely conditioned by the primary structure of the peptide. A beta nac containing the sequence 1-40, 1-42 or bearing amino acid substitutions (Dutch variant of A beta) was protease-sensitive and unable to form a significant amount of amyloid even at high concentrations or after long incubations. The finding of the simultaneous existence of different A beta conformers with distinct abilities to form amyloid may help to explain why A beta is found in both soluble and fibrillar forms in vivo.

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Selected References

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  1. Barrow C. J., Yasuda A., Kenny P. T., Zagorski M. G. Solution conformations and aggregational properties of synthetic amyloid beta-peptides of Alzheimer's disease. Analysis of circular dichroism spectra. J Mol Biol. 1992 Jun 20;225(4):1075–1093. doi: 10.1016/0022-2836(92)90106-t. [DOI] [PubMed] [Google Scholar]
  2. Barrow C. J., Zagorski M. G. Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition. Science. 1991 Jul 12;253(5016):179–182. doi: 10.1126/science.1853202. [DOI] [PubMed] [Google Scholar]
  3. Beaven G. H., Gratzer W. B., Davies H. G. Formation and structure of gels and fibrils from glucagon. Eur J Biochem. 1969 Nov;11(1):37–42. doi: 10.1111/j.1432-1033.1969.tb00735.x. [DOI] [PubMed] [Google Scholar]
  4. Burdick D., Soreghan B., Kwon M., Kosmoski J., Knauer M., Henschen A., Yates J., Cotman C., Glabe C. Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. J Biol Chem. 1992 Jan 5;267(1):546–554. [PubMed] [Google Scholar]
  5. Bush A. I., Pettingell W. H., Multhaup G., d Paradis M., Vonsattel J. P., Gusella J. F., Beyreuther K., Masters C. L., Tanzi R. E. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994 Sep 2;265(5177):1464–1467. doi: 10.1126/science.8073293. [DOI] [PubMed] [Google Scholar]
  6. Castano E. M., Prelli F., Wisniewski T., Golabek A., Kumar R. A., Soto C., Frangione B. Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E. Biochem J. 1995 Mar 1;306(Pt 2):599–604. doi: 10.1042/bj3060599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Castaño E. M., Ghiso J., Prelli F., Gorevic P. D., Migheli A., Frangione B. In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer's disease beta-protein. Biochem Biophys Res Commun. 1986 Dec 15;141(2):782–789. doi: 10.1016/s0006-291x(86)80241-8. [DOI] [PubMed] [Google Scholar]
  8. Clements A., Walsh D. M., Williams C. H., Allsop D. Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid beta/A4 peptide. Neurosci Lett. 1993 Oct 14;161(1):17–20. doi: 10.1016/0304-3940(93)90129-9. [DOI] [PubMed] [Google Scholar]
  9. Dyrks T., Dyrks E., Hartmann T., Masters C., Beyreuther K. Amyloidogenicity of beta A4 and beta A4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem. 1992 Sep 5;267(25):18210–18217. [PubMed] [Google Scholar]
  10. Dyson H. J., Merutka G., Waltho J. P., Lerner R. A., Wright P. E. Folding of peptide fragments comprising the complete sequence of proteins. Models for initiation of protein folding. I. Myohemerythrin. J Mol Biol. 1992 Aug 5;226(3):795–817. doi: 10.1016/0022-2836(92)90633-u. [DOI] [PubMed] [Google Scholar]
  11. Dyson H. J., Rance M., Houghten R. A., Lerner R. A., Wright P. E. Folding of immunogenic peptide fragments of proteins in water solution. I. Sequence requirements for the formation of a reverse turn. J Mol Biol. 1988 May 5;201(1):161–200. doi: 10.1016/0022-2836(88)90446-9. [DOI] [PubMed] [Google Scholar]
  12. Exley C., Price N. C., Kelly S. M., Birchall J. D. An interaction of beta-amyloid with aluminium in vitro. FEBS Lett. 1993 Jun 21;324(3):293–295. doi: 10.1016/0014-5793(93)80137-j. [DOI] [PubMed] [Google Scholar]
  13. Fabian H., Szendrei G. I., Mantsch H. H., Otvos L., Jr Comparative analysis of human and Dutch-type Alzheimer beta-amyloid peptides by infrared spectroscopy and circular dichroism. Biochem Biophys Res Commun. 1993 Feb 26;191(1):232–239. doi: 10.1006/bbrc.1993.1207. [DOI] [PubMed] [Google Scholar]
  14. Fraser P. E., McLachlan D. R., Surewicz W. K., Mizzen C. A., Snow A. D., Nguyen J. T., Kirschner D. A. Conformation and fibrillogenesis of Alzheimer A beta peptides with selected substitution of charged residues. J Mol Biol. 1994 Nov 18;244(1):64–73. doi: 10.1006/jmbi.1994.1704. [DOI] [PubMed] [Google Scholar]
  15. Fraser P. E., Nguyen J. T., Chin D. T., Kirschner D. A. Effects of sulfate ions on Alzheimer beta/A4 peptide assemblies: implications for amyloid fibril-proteoglycan interactions. J Neurochem. 1992 Oct;59(4):1531–1540. doi: 10.1111/j.1471-4159.1992.tb08470.x. [DOI] [PubMed] [Google Scholar]
  16. Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
  17. Gorevic P. D., Castano E. M., Sarma R., Frangione B. Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic x-ray diffraction pattern. Biochem Biophys Res Commun. 1987 Sep 15;147(2):854–862. doi: 10.1016/0006-291x(87)91008-4. [DOI] [PubMed] [Google Scholar]
  18. Hamazaki H. Amyloid P component promotes aggregation of Alzheimer's beta-amyloid peptide. Biochem Biophys Res Commun. 1995 Jun 15;211(2):349–353. doi: 10.1006/bbrc.1995.1819. [DOI] [PubMed] [Google Scholar]
  19. Hilbich C., Kisters-Woike B., Reed J., Masters C. L., Beyreuther K. Aggregation and secondary structure of synthetic amyloid beta A4 peptides of Alzheimer's disease. J Mol Biol. 1991 Mar 5;218(1):149–163. doi: 10.1016/0022-2836(91)90881-6. [DOI] [PubMed] [Google Scholar]
  20. Hilbich C., Kisters-Woike B., Reed J., Masters C. L., Beyreuther K. Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease beta A4 peptides. J Mol Biol. 1992 Nov 20;228(2):460–473. doi: 10.1016/0022-2836(92)90835-8. [DOI] [PubMed] [Google Scholar]
  21. Hubbard S. J., Eisenmenger F., Thornton J. M. Modeling studies of the change in conformation required for cleavage of limited proteolytic sites. Protein Sci. 1994 May;3(5):757–768. doi: 10.1002/pro.5560030505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jarrett J. T., Berger E. P., Lansbury P. T., Jr The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry. 1993 May 11;32(18):4693–4697. doi: 10.1021/bi00069a001. [DOI] [PubMed] [Google Scholar]
  23. Kamino K., Orr H. T., Payami H., Wijsman E. M., Alonso M. E., Pulst S. M., Anderson L., O'dahl S., Nemens E., White J. A. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992 Nov;51(5):998–1014. [PMC free article] [PubMed] [Google Scholar]
  24. Kirschner D. A., Inouye H., Duffy L. K., Sinclair A., Lind M., Selkoe D. J. Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6953–6957. doi: 10.1073/pnas.84.19.6953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Levy E., Carman M. D., Fernandez-Madrid I. J., Power M. D., Lieberburg I., van Duinen S. G., Bots G. T., Luyendijk W., Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124–1126. doi: 10.1126/science.2111584. [DOI] [PubMed] [Google Scholar]
  26. Ma J., Yee A., Brewer H. B., Jr, Das S., Potter H. Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature. 1994 Nov 3;372(6501):92–94. doi: 10.1038/372092a0. [DOI] [PubMed] [Google Scholar]
  27. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. May P. C., Gitter B. D., Waters D. C., Simmons L. K., Becker G. W., Small J. S., Robison P. M. beta-Amyloid peptide in vitro toxicity: lot-to-lot variability. Neurobiol Aging. 1992 Sep-Oct;13(5):605–607. doi: 10.1016/0197-4580(92)90064-5. [DOI] [PubMed] [Google Scholar]
  29. Müller-Hill B., Beyreuther K. Molecular biology of Alzheimer's disease. Annu Rev Biochem. 1989;58:287–307. doi: 10.1146/annurev.bi.58.070189.001443. [DOI] [PubMed] [Google Scholar]
  30. Naiki H., Higuchi K., Nakakuki K., Takeda T. Kinetic analysis of amyloid fibril polymerization in vitro. Lab Invest. 1991 Jul;65(1):104–110. [PubMed] [Google Scholar]
  31. Nordstedt C., Näslund J., Tjernberg L. O., Karlström A. R., Thyberg J., Terenius L. The Alzheimer A beta peptide develops protease resistance in association with its polymerization into fibrils. J Biol Chem. 1994 Dec 9;269(49):30773–30776. [PubMed] [Google Scholar]
  32. Osterhout J. J., Jr, Baldwin R. L., York E. J., Stewart J. M., Dyson H. J., Wright P. E. 1H NMR studies of the solution conformations of an analogue of the C-peptide of ribonuclease A. Biochemistry. 1989 Aug 22;28(17):7059–7064. doi: 10.1021/bi00443a042. [DOI] [PubMed] [Google Scholar]
  33. Pan K. M., Baldwin M., Nguyen J., Gasset M., Serban A., Groth D., Mehlhorn I., Huang Z., Fletterick R. J., Cohen F. E. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962–10966. doi: 10.1073/pnas.90.23.10962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Perczel A., Park K., Fasman G. D. Analysis of the circular dichroism spectrum of proteins using the convex constraint algorithm: a practical guide. Anal Biochem. 1992 May 15;203(1):83–93. doi: 10.1016/0003-2697(92)90046-a. [DOI] [PubMed] [Google Scholar]
  35. Price D. L., Borchelt D. R., Walker L. C., Sisodia S. S. Toxicity of synthetic A beta peptides and modeling of Alzheimer's disease. Neurobiol Aging. 1992 Sep-Oct;13(5):623–625. doi: 10.1016/0197-4580(92)90069-a. [DOI] [PubMed] [Google Scholar]
  36. Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D., Sinha S., Schlossmacher M., Whaley J., Swindlehurst C. Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature. 1992 Sep 24;359(6393):325–327. doi: 10.1038/359325a0. [DOI] [PubMed] [Google Scholar]
  37. Shoji M., Golde T. E., Ghiso J., Cheung T. T., Estus S., Shaffer L. M., Cai X. D., McKay D. M., Tintner R., Frangione B. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992 Oct 2;258(5079):126–129. doi: 10.1126/science.1439760. [DOI] [PubMed] [Google Scholar]
  38. Simmons L. K., May P. C., Tomaselli K. J., Rydel R. E., Fuson K. S., Brigham E. F., Wright S., Lieberburg I., Becker G. W., Brems D. N. Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. Mol Pharmacol. 1994 Mar;45(3):373–379. [PubMed] [Google Scholar]
  39. Sorimachi K., Craik D. J. Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch-type hereditary cerebral haemorrhage with amyloidosis. Eur J Biochem. 1994 Jan 15;219(1-2):237–251. doi: 10.1111/j.1432-1033.1994.tb19935.x. [DOI] [PubMed] [Google Scholar]
  40. Soto C., Brañes M. C., Alvarez J., Inestrosa N. C. Structural determinants of the Alzheimer's amyloid beta-peptide. J Neurochem. 1994 Oct;63(4):1191–1198. doi: 10.1046/j.1471-4159.1994.63041191.x. [DOI] [PubMed] [Google Scholar]
  41. Soto C., Castaño E. M., Frangione B., Inestrosa N. C. The alpha-helical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation. J Biol Chem. 1995 Feb 17;270(7):3063–3067. doi: 10.1074/jbc.270.7.3063. [DOI] [PubMed] [Google Scholar]
  42. Soto C., Castaño E. M., Kumar R. A., Beavis R. C., Frangione B. Fibrillogenesis of synthetic amyloid-beta peptides is dependent on their initial secondary structure. Neurosci Lett. 1995 Nov 17;200(2):105–108. doi: 10.1016/0304-3940(95)12089-m. [DOI] [PubMed] [Google Scholar]
  43. Soto C., Frangione B. Two conformational states of amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neurosci Lett. 1995 Feb 17;186(2-3):115–118. doi: 10.1016/0304-3940(95)11299-c. [DOI] [PubMed] [Google Scholar]
  44. Talafous J., Marcinowski K. J., Klopman G., Zagorski M. G. Solution structure of residues 1-28 of the amyloid beta-peptide. Biochemistry. 1994 Jun 28;33(25):7788–7796. doi: 10.1021/bi00191a006. [DOI] [PubMed] [Google Scholar]
  45. Tennent G. A., Lovat L. B., Pepys M. B. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4299–4303. doi: 10.1073/pnas.92.10.4299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Terzi E., Hölzemann G., Seelig J. Reversible random coil-beta-sheet transition of the Alzheimer beta-amyloid fragment (25-35). Biochemistry. 1994 Feb 15;33(6):1345–1350. doi: 10.1021/bi00172a009. [DOI] [PubMed] [Google Scholar]
  47. Tomiyama T., Asano S., Furiya Y., Shirasawa T., Endo N., Mori H. Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues. J Biol Chem. 1994 Apr 8;269(14):10205–10208. [PubMed] [Google Scholar]
  48. Wisniewski T., Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992 Feb 3;135(2):235–238. doi: 10.1016/0304-3940(92)90444-c. [DOI] [PubMed] [Google Scholar]
  49. Wisniewski T., Ghiso J., Frangione B. Alzheimer's disease and soluble A beta. Neurobiol Aging. 1994 Mar-Apr;15(2):143–152. doi: 10.1016/0197-4580(94)90105-8. [DOI] [PubMed] [Google Scholar]
  50. Wisniewski T., Ghiso J., Frangione B. Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1247–1254. doi: 10.1016/0006-291x(91)91706-i. [DOI] [PubMed] [Google Scholar]
  51. Wright P. E., Dyson H. J., Lerner R. A. Conformation of peptide fragments of proteins in aqueous solution: implications for initiation of protein folding. Biochemistry. 1988 Sep 20;27(19):7167–7175. doi: 10.1021/bi00419a001. [DOI] [PubMed] [Google Scholar]
  52. Zagorski M. G., Barrow C. J. NMR studies of amyloid beta-peptides: proton assignments, secondary structure, and mechanism of an alpha-helix----beta-sheet conversion for a homologous, 28-residue, N-terminal fragment. Biochemistry. 1992 Jun 23;31(24):5621–5631. doi: 10.1021/bi00139a028. [DOI] [PubMed] [Google Scholar]

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