The A beta 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater beta-sheet forming and aggregation propensities in vitro than full-length A beta.
A beta isolated from neuritic plaque and vascular walls of the brains of patients with Alzheimer's disease has been shown to contain significant quantities of A beta peptides which begin at residue 3Glu or 11Glu in the form of pyroglutamyl residues (A beta 3pE and A beta 11pE). To investigate the effects of these N-terminal modifications on the biophysical properties of A beta, peptides A beta 1-40, A beta 3pE-40, A beta 11pE-40, A beta 1-28, A beta 3pE-28, and A beta 11pE-28 were synthesized. Using circular dichroism spectroscopy, we determined that the pyroglutamyl-containing peptides form beta-sheet structure more readily than the corresponding full-length A beta peptides, both in aqueous solutions and in 10% sodium dodecyl sulfate micelles. Trifluoroethanol spectra indicated that the relative beta-sheet to alpha-helical stability is higher for the pyroglutamyl-containing peptides. Sedimentation experiments show that the pyroglutamyl-containing peptides have greater aggregation propensities than the corresponding full-length peptides. Comparison between the A beta 40 and the A beta 28 series indicated that the greater beta-sheet forming and aggregation propensities of the pyroglutamyl peptides are not simply due to an increase in hydrophobicity.
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School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia.
Barrow
C J
CJ
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate; D012996:Solutions
D016229:Amyloid beta-Peptides; D008823:Micelles; D010446:Peptide Fragments; D012996:Solutions; C084358:amyloid beta-protein (1-28); C078592:amyloid beta-protein (1-40); D012967:Sodium Dodecyl Sulfate; D018698:Glutamic Acid