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

The A beta(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 A beta(1-42) assembly and could influence the occurrence and pathophysiology of AD. However, pesticide involvement in the early stages of A beta (1-42) aggregation is still unknown. Here, we employed conical track-etched nanopore in order to analyse the A beta (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 A beta(1-42). A beta(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 A beta(1-42) mechanism in two steps including the reorganization prior the elongation phase.