Formation of Dynamic Soluble Surfactant-Induced Amyloid Beta Peptide Aggregation Intermediates

Abstract

The 40-42 residue Amyloid β (Aβ) peptide forms β-structured oligomers on-pathway to amyloid fibril formation and are linked to neuronal damage characteristic for Alzheimer's disease. Surfactants such as SDS induce relatively stable β-structured Aβ co-aggregates and may be considered as a model system for lipids. We have characterized different intermediate aggregation states appearing during the Aβ aggregation process, as well as the kinetics of their formation and dynamic exchange between free and bound peptide. A broad range of biophysical techniques were used, including small angle X-ray scattering (SAXS) and NMR spectroscopy, particularly 15N-CPMG relaxation dispersion experiments. Aβ shows a three-state secondary structure transition depending on surfactant concentration, from random coil-like, via β-structure to α-helix at high surfactant concentration. Structural information on the β-structured co-aggregates was obtained by SAXS experiments that at the beginning showed a large fraction of globular co-aggregates (diameter ∼ 75 Å). This fraction gradually vanished on a min to hr timescale and elongated co-aggregated fibrils were formed (diameter ∼ 60 Å and length > 350 Å), in line with transmission electron microscopy images. A fast dynamic exchange process (kex ∼ 1100 s-1) between free and co-aggregate bound peptide takes place, as monitored by NMR relaxation dispersion experiments. This study of the surfactant-induced Aβ aggregation may serve as a model for aggregation of Aβ alone or in the presence of lipids. Reference: 1. Abelein, A. et al., J. Biol. Chem. (2013), 288, 23518-23528.