Effect of Cross-Seeding of Wild-Type Amyloid-β1-40 Peptides with Post-translationally Modified Fibrils on Internal Dynamics of the Fibrils Using Deuterium Solid-State NMR.

Abstract

Post-translationally modified (PTM) amyloid-β (Aβ) species can play an important role in modulating Alzheimer's disease pathology. These relatively less populated modifications can cross-seed the wild-type Aβ peptides to produce fibrils that retain many structural and functional features of the original PTM variants. We focus on studies of internal flexibility in the cross-seeded Aβ1-40 fibrils originating from seeding with two PTM variants with modifications in the disordered N-terminal domain: ΔE3 truncation and S8-phosphorylation. We employ an array of 2H solid-state NMR techniques, including line shape analysis over a broad temperature range, longitudinal relaxation, and quadrupolar CPMG, to assess the dynamics of the cross-seeded fibrils. The focus is placed on selected side-chain sites in the disordered N-terminal domain (G9 and V12) and hydrophobic core methyl and aromatic groups (L17, L34, M35, V36, and F19). We find that many of the essential features of the dynamics present in the original PTM seeds persist in the cross-seeded fibrils, and several of the characteristic features are even enhanced. This is particularly true for the activation energies of the rotameric motions and large-scale rearrangements of the N-terminal domain. Thus, our results on the dynamics complement prior structural and cell toxicity studies, suggesting that many PTM Aβ species can aggressively cross-seed the wild-type peptide in a manner that propagates the PTM's signature.