Conical nanopores highlight the pro-aggregating effects of pyrimethanil fungicide on Aβ(1–42) peptides and dimeric splitting phenomena

Abstract

The Aβ(1–42) aggregation is a key event in the physiopathology of Alzheimer's disease (AD). Exogenous factors such as environmental pollutants, and more particularly pesticides, can corrupt Aβ(1–42) assembly and could influence the occurrence and pathophysiology of AD. However, pesticide involvement in the early stages of Aβ(1–42) aggregation is still unknown. Here, we employed conical track-etched nanopore in order to analyse the Aβ(1–42) fibril formation in the presence of pyrimethanil, a widely used fungicide belonging to the anilinopyrimidine class. Our results evidenced a pro-aggregating effect of pyrimethanil on Aβ(1–42). Aβ(1–42) assemblies were successfully detected using conical nanopore coated with PEG. Using an analytical model, the large current blockades observed (>0.7) were assigned to species with size close to the sensing pore. The long dwell times (hundreds ms scale) were interpreted by the possible interactions amyloid/PEG using molecular dynamic simulation. Such interaction could leave until splitting phenomena of the dimer structure. Our work also evidences that the pyrimethanil induce an aggregation of Aβ(1–42) mechanism in two steps including the reorganization prior the elongation phase.