Amyloid β (Aβ) peptide aggregates are linked to Alzheimer's disease (AD). Posttranslationally pyroglutamylated Aβ (pEAβ) occurs in AD brains in significant quantities and is hypertoxic, but the underlying structural and aggregation properties remain poorly understood. Here, the structure and aggregation of Aβ1-40 and pEAβ3-40 are analyzed separately and in equimolar combination. Circular dichroism data show that Aβ1-40 , pEAβ3-40 , and their combination assume α-helical structure in dry state and transition to unordered structure in aqueous buffer. Aβ1-40 and the 1:1 combination gradually acquire β-sheet structure while pEAβ3-40 adopts an α-helix/β-sheet conformation. Thioflavin-T fluorescence studies suggest that the two peptides mutually inhibit fibrillogenesis. Fourier transform infrared (FTIR) spectroscopy identifies the presence of β-turn and α-helical structures in addition to β-sheet structure in peptides in aqueous buffer. The kinetics of transitions from the initial α-helical structure to β-sheet structure were resolved by slow hydration of dry peptides by D2 O vapor, coupled with isotope-edited FTIR. These data confirmed the mutual suppression of β-sheet formation by the two peptides. Remarkably, pEAβ3-40 maintained a significant fraction of α-helical structure in the combined sample, implying a reduced β-sheet propensity of pEAβ3-40 . Altogether, the data imply that the combination of unmodified and pyroglutamylated Aβ peptides resists fibrillogenesis and favors the prefibrillar state, which may underlie hypertoxicity of pEAβ.
Keywords: aggregation; amyloid β; structural transitions; structure.
© 2021 European Peptide Society and John Wiley & Sons, Ltd.