Résumé
This study investigated the impact of pyrimethanil, a fungicide, on the aggregation of amyloid-β 42 (aβ42) peptides in vitro. The findings demonstrated that pyrimethanil accelerated aβ42 aggregation kinetics, as evidenced by thioflavin T (ThT) fluorescence assays in both tube and microplate experiments. A combination of single molecule techniques and molecular dynamics simulations is used to elucidate the complex effects of pyrimethanil on aβ42 aggregation mechanism. Nanopore experiments indicated that pyrimethanil promoted the formation of small oligomers (6-13.5 nm) during the lag phase, which were not detected under control conditions. Confocal fluorescence spectroscopy revealed that pyrimethanil induced the formation of larger β-sheet structured aggregates. In the presence of preformed seeds, pyrimethanil exhibited a dual role by fragmenting existing fibrils into smaller species and enhancing aggregation, likely through combined effects with the newly formed smaller seeds. Molecular dynamics simulations confirmed that pyrimethanil has a higher affinity for fibrils than monomers and weakens monomer-fibril interactions. Overall, this study elucidates the complex effects of pyrimethanil on aβ42 aggregation, involving promotion of primary nucleation, fibril fragmentation, and modulation of monomer-fibril interactions. These findings provide important mechanistic insights into how environmental factors like pesticides may influence amyloid aggregation processes relevant to Alzheimer's disease.
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•Pyrimethanil accelerates Aβ42 aggregation kinetics.•Pyrimethanil promotes small oligomers (6-13.5 nm) during the lag phase.•Pyrimethanil induces larger β-sheet structured aggregates.•Pyrimethanil fragments fibrils and enhances aggregation with seeds.•Pyrimethanil has higher affinity for fibrils, weakens monomer-fibril interactions.