Spontaneous formation of β-sheet nano-barrels during the early aggregation of Alzheimer's amyloid beta

Soluble low-molecular-weight oligomers formed during the early aggregation of amyloid peptides have been hypothesized as a major toxic species of amyloidogenesis. Herein, we performed the first synergic in silico, in vitro and in vivo validations of the structure, dynamics and toxicity of A beta 42 oligomers. A beta peptides readily assembled into beta-rich oligomers comprised of extended beta-hairpins and beta-strands. Nanosized beta-barrels were observed with certainty with simulations, transmission electron microscopy and Fourier transform infrared spectroscopy, corroborated by immunohistochemistry, cell viability, apoptosis, inflammation, autophagy and animal behavior assays. Secondary and tertiary structural properties of these oligomers, such as the sequence regions with high beta-sheet propensities and inter-residue contact frequency patterns, were similar to the properties known for A beta fibrils. The unambiguous spontaneous formation of beta-barrels in the early aggregation of A beta 42 supports their roles as the common toxic intermediates in Alzheimer pathobiology and a target for Alzheimers therapeutics. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

This study provides evidence of the structure, dynamics and toxicity of A beta 42 oligomers through synergistic in silico, in vitro and in vivo validations, highlighting their role as toxic intermediates in the early aggregation of amyloid peptides.