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Comparative fibril formation of analogs corresponding to the (12–24) segment of the β-amyloid peptide


The (1–42) β-amyloid peptide is a main component of the plaques found in the brain of patients suffering from the Alzheimer’s disease. As the single substitution of Glu for Gln at position 22 of this peptide seems to be responsible for the manifestation of the more severe amyloidosis (Dutch-type), we decided to evaluate the aggregation characteristics of peptide analogs interchanging Glu and Gln residues at positions 22 and also 15 in the minor (12–24) (VHHQ15KLVFFAE22DV) fragment. The Q15Q22, E15E22, E15Q22 and the native Q15E22 were compared to the (1–42) β-amyloid peptide in terms of fibril or structured aggregates formation propensity. In contrast to a rather similar solubility data measured of all analogs, fluorescence and light scattering methods indicated that only Q15E22 and Q15Q22 displayed relevant fibril formation capacity. Conversely, E15E22 and E15Q22 were not capable of the formation of this type of structure thus suggesting a key role for the Q15 residue in the unique aggregation characteristic of the β-amyloid peptide.

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High-performance liquid chromatography


Liquid chromatography/mass spectrometry


Methylbenzhydrylamine resin










2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate




Trifluoroacetic acid


Thioflavine T




  1. Harper JD, Lansburry PT Jr (1997) Models of amyloid seeding in Alzheimer′s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Ann Rev Biochem 66:385–407

    PubMed  Article  CAS  Google Scholar 

  2. Lynn DG, Meredith SC (2000) Model peptides and the physico-chemical approach to β-amyloid. J Struc Biol 130:153–173

    Article  CAS  Google Scholar 

  3. Ferreira ST, Vieira MNN, De Felice FG (2007) Soluble protein oligomers as emerging toxins in Alzheimer’s and other amyloid diseases. IUBMB Life 59:332–345

    PubMed  Article  CAS  Google Scholar 

  4. Soto C, Frangione B (1995) Two conformational states of amyloid β-peptide: implications for the pathogenesis of Alzheimer′s disease. Neurosci Lett 186:115–118

    PubMed  Article  CAS  Google Scholar 

  5. Koo EH, Lansbury PT Jr, Kelly JW (1999) Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc Natl Acad Sci 96:9989–9990

    PubMed  Article  CAS  Google Scholar 

  6. De-Felice FG, Vieira MNN, Saraiva LM, Figueroa-Villar JD, Garcia-Abreu J, Liu R, Chang L, Klein WL, Ferreira ST (2004) Targeting the neurotoxic species in Alzheimer′s disease: inhibitors of Aβ-oligomerization. Faseb J 18:1366–1372

    PubMed  Article  CAS  Google Scholar 

  7. Tjernberg LO, Callaway DJE, Tjernberg A, Hahne S, Lillichook C, Terenius L, Thyberg J, Nordsted C (1999) A molecular model of Alzheimer amyloid β-peptide fibril formation. J Biol Chem 274:12619–12625

    PubMed  Article  CAS  Google Scholar 

  8. Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tyeko R (2000) Amyloid fibril formation by Aβ16–22, a seven-residue fragment of the Alzheimer’s β-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39:13748–13759

    PubMed  Article  CAS  Google Scholar 

  9. Levy E, Carman MD, Fernandez-Madri IJ, Power MD, Lieberburg I, van Duinen SG, Bota GT, Lyyendijk W, Frangione B (1990) Mutation of the Alzheimer′s disease amyloid gene in hereditary cerebral hemorrhage Dutch-type. Science 248:1124–1126

    PubMed  Article  CAS  Google Scholar 

  10. Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J (2000) Substitution at codon 22 of Alzheimer′s Abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem 275:27110–27116

    PubMed  CAS  Google Scholar 

  11. Esler WP, Felix AM, Stimson ER, Lachenmannn MJ, Ghilardi JR, Lu Y, Vinters HV, Mantyh PW, Lee JP, Maggio JE (2000) Activation barrier to structural transition determine deposition rates of Alzheimer′s disease. J Struct Biol 130:174–183

    PubMed  Article  CAS  Google Scholar 

  12. Herzig MC, Eisele YS, Staufenbiel M, Jucker M (2009) E22Q-mutant Abeta peptide (AbetaDutch) increases vascular but reduces parenchymal Abeta deposition. Am J Pathol 174:722–726

    PubMed  Article  CAS  Google Scholar 

  13. Massi F, Straub JE (2001) Probing the origins of increased activity of the E22Q “Dutch” mutant Alzheimer’s β-amyloid peptide. Biophys J 81:697–709

    PubMed  Article  CAS  Google Scholar 

  14. Massi F, Kimov D, Thirumalai D, Straub JE (2002) Charge states rather than propensity for beta-structure determine enhanced fibrillogenesis in wild-type Alzheimer′s beta-amyloid peptide compared to E22Q Dutch mutant. Protein Sci 11:1639–1647

    PubMed  Article  CAS  Google Scholar 

  15. Malavolta L, Nakaie CR (2004) Peptide dissociation in solution or bound to a polymer: comparative solvent effect. Tetrahedron 60:9417–9424

    Article  CAS  Google Scholar 

  16. Malavolta L, Pinto MRS, Cuvero JH, Nakaie CR (2006) Interpretation of the dissolution of insoluble peptide sequences based on the acid-base properties of the solvent. Protein Sci 15:1476–1488

    PubMed  Article  CAS  Google Scholar 

  17. Matsueda GR, Stewart JM (1981) A p-methylbenzhydrylamine-resin for improved solid phase synthesis of peptide amides. Peptides 2:45–50

    PubMed  Article  CAS  Google Scholar 

  18. Marchetto R, Etchegaray A, Nakaie CR (1992) Kinetics of synthesis and swelling studies of highly substituted benzhydrylamine-resins: implications for peptide synthesis and perspectives for use as anion exchanger resin. J Braz Chem Soc 3:30–37

    CAS  Google Scholar 

  19. Barany G, Merrifield RB (1980) Solid-phase peptide synthesis. In: Gross E, Meienhofer J (eds) The peptides: analysis, synthesis and biology, vol 2. Academic Press, New York, pp 1–284

    Google Scholar 

  20. Kates SA, Albericio F (2000) Solid phase synthesis: a practical guide. Marcel Dekker, New York, pp 275–330

    Google Scholar 

  21. Levine H (1993) Thioflavine T interaction with synthetic Alzheimer′s disease β-amyloid peptides: Detection of amyloid aggregation in solution. Protein Sci 2:404–410

    PubMed  Article  CAS  Google Scholar 

  22. Meinhardt J, Tartaglia GG, Pawar A, Christopeit T, Hortschansky P, Schroeckh V, Dobson CM, Vendruscolo M, Fändrich M (2007) Similarities in the thermodynamics and kinetics of aggregation of disease related Aβ(1–40) peptides. Protein Sci 16:1214–1222

    PubMed  Article  CAS  Google Scholar 

  23. Orte A, Birkett N, Clarke RW, Devlin GL, Dobson CM, Klenerman D (2008) Direct characterization of amyloidogenic oligomers by single-molecule fluorescence. Proc Natl Acad Sci 105:14424–14429

    PubMed  Article  CAS  Google Scholar 

  24. Carulla N, Zhou M, Arimon M, Gairi M, Giralt E, Robinson CV (2009) Experimental characterization of disordered and ordered aggregates populated during the process of amyloid fibril formation. Proc Natl Acad Sci 106:7828–7833

    PubMed  Article  CAS  Google Scholar 

  25. Baumketner A, Shea JE (2007) The structure of the Alzheimer amyloid beta 10–35 peptide probed through replica-exchange molecular dynamics simulations in explicit solvents. J Mol Biol 366:275–285

    PubMed  Article  CAS  Google Scholar 

  26. Baumketner A, Krone MG, Shea JE (2008) Role of familiar Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-beta protein. Proc Natl Acad Sci 105:6027–6032

    PubMed  Article  CAS  Google Scholar 

  27. Han W, Wu YD (2007) Molecular dynamics studies of hexamers of amyloid-beta peptide (16–35) and its mutants: influence of charge states on amyloid formation. Proteins 66:575–587

    PubMed  Article  CAS  Google Scholar 

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Grants from the Brazilian governmental agencies FAPESP, CNPq and UNIEMP are gratefully acknowledged.

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Correspondence to Clóvis R. Nakaie.

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Luciana Malavolta is a fellow of UNIEMP and Clóvis R. Nakaie is a recipient of research fellowships from CNPq and FADA.

Abbreviations for amino acids and nomenclature of peptide structure follow the recommendations of IUPAC-IUB (Commission on Biochemical Nomenclature) (J. Biol. Chem. 1971, 247, 997).

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Malavolta, L., Nakaie, C.R. Comparative fibril formation of analogs corresponding to the (12–24) segment of the β-amyloid peptide. Neurol Sci 32, 1123–1127 (2011).

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  • Peptide
  • Amyloidosis
  • Fibril formation
  • Alzheimer’s disease
  • β-amyloid peptide