Exploring the Early Stages of the Amyloid Aβ(1-42) Peptide Aggregation Process: An NMR Study

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of neurofibrillary tangles and amyloid plaques, the latter mainly composed of A beta(1-40) and A beta(1-42) peptides. The control of the A beta aggregation process as a therapeutic strategy for AD has prompted the interest to investigate the conformation of the A beta peptides, taking advantage of computational and experimental techniques. Mixtures composed of systematically different proportions of HFIP and water have been used to monitor, by NMR, the conformational transition of the A beta(1-42) from soluble alpha-helical structure to beta-sheet aggregates. In the previous studies, 50/50 HFIP/water proportion emerged as the solution condition where the first evident A beta(1-42) conformational changes occur. In the hypothesis that this solvent reproduces the best condition to catch transitional helical-beta-sheet A beta(1-42) conformations, in this study, we report an extensive NMR conformational analysis of A beta(1-42) in 50/50 HFIP/water v/v. A beta(1-42) structure was solved by us, giving evidence that the evolution of A beta(1-42) peptide from helical to the beta-sheet may follow unexpected routes. Molecular dynamics simulations confirm that the structural model we calculated represents a starting condition for amyloid fibrils formation.

Automated summary

This study utilized NMR to analyze the conformational transition of A beta(1-42) in 50/50 HFIP/water, revealing unexpected routes in the evolution from helical to beta-sheet structures. Molecular dynamics simulations confirmed that the structural model calculated in this study is a starting point for amyloid fibrils formation.