The Aβ 3-Pyroglutamyl and 11-Pyroglutamyl Peptides Found in Senile Plaque Have Greater β-Sheet Forming and Aggregation Propensities in Vitro than Full-Length Aβ

Abstract

Aβ isolated from neuritic plaque and vascular walls of the brains of patients with Alzheimer's disease has been shown to contain significant quantities of Aβ peptides which begin at residue ³Glu or ¹¹Glu in the form of pyroglutamyl residues (Aβ3pE and Aβ11pE). To investigate the effects of these N-terminal modifications on the biophysical properties of Aβ, peptides Aβ1−40, Aβ3pE−40, Aβ11pE−40, Aβ1−28, Aβ3pE−28, and Aβ11pE−28 were synthesized. Using circular dichroism spectroscopy, we determined that the pyroglutamyl-containing peptides form β-sheet structure more readily than the corresponding full-length Aβ peptides, both in aqueous solutions and in 10% sodium dodecyl sulfate micelles. Trifluoroethanol spectra indicated that the relative β-sheet to α-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 Aβ40 and the Aβ28 series indicated that the greater β-sheet forming and aggregation propensities of the pyroglutamyl peptides are not simply due to an increase in hydrophobicity.