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

Abstract

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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Abbreviations

Boc:

tert-Butyloxycarbonyl

2-ClZ:

2-Chlorobenzyloxicarbonyl

DCM:

Dichloromethane

DIC:

Diisopropylcarbodiimide

DIEA:

Diisopropylethylamine

DMF:

N,N′-Dimethylformamide

DMSO:

Dimethylsulfoxide

HOBt:

1-Hydroxybenzotriazole

HPLC:

High-performance liquid chromatography

LC/MS:

Liquid chromatography/mass spectrometry

MBHAR:

Methylbenzhydrylamine resin

MeCN:

Acetonitrile

MeOH:

Methanol

NMP:

N-Methylpiperidine

OcHex:

Cyclohexylester

TBTU:

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

TEA:

Triethylamine

TFA:

Trifluoroacetic acid

ThT:

Thioflavine T

Tos:

p-Toluenesulfonyl

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Acknowledgments

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

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Correspondence to Clóvis R. Nakaie.

Additional information

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). https://doi.org/10.1007/s10072-011-0749-3

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  • DOI: https://doi.org/10.1007/s10072-011-0749-3

Keywords

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