Static and dynamic disorder in Aβ40 fibrils

Abstract

Deposition of Aβ aggregates in the form of amyloid fibrils is a pathological hallmark of Alzheimer's disease. Understanding the structure and dynamics of Aβ fibrils is important for delineating the mechanism of Aβ aggregation and developing effective therapeutic strategies. Here we used site-directed spin labeling and EPR spectroscopy to study the Aβ40 fibril structure and dynamics. We obtained the EPR spectra of 40 spin-labeled Aβ40 fibril samples, with spin labeling coverage of the entire Aβ40 sequence. Analysis of the spin exchange interaction and spin label mobility using spectral simulations suggest that the strength of spin exchange interaction is primarily determined by static disorder in the Aβ40 fibrils. EPR data suggest that the entire Aβ40 sequence except residue D1 is highly ordered and the two hydrophobic regions at residues 17–20 and 31–36 show the lowest static disorder. Dynamic disorder is relatively constant across all reside positions, with residues 22 and 23 having the highest dynamic disorder. Comparison of the EPR data for Aβ40 and Aβ42 fibrils shows overall more ordered packing interactions in Aβ40 fibrils. Another noteworthy difference is the C-terminal residue, which has high static disorder in Aβ42 fibrils, but is ordered in Aβ40 fibrils. The higher static disorder in Aβ42 fibrils may lead to increased fragmentation, monomer dissociation, and structural defects, which may contribute to increased aggregation through secondary nucleation.