Electrochemistry Reveals the Accelerating Effect of Fluorinated Compounds on Early-Stage Amyloid Fibril Aggregation

Fluorinated compounds, which are widely used and environmentally persistent, represent important potential triggers of amyloid fibril aggregation associated with neurodegenerative diseases. However, their specific effects on early-stage oligomers and protofibrils remain poorly understood. Research progress is constrained by conventional analytical methods due to the inability to monitor dynamics in aqueous environments and insufficient sensitivity for detecting early aggregates with limited β-sheet content, existing in an irregular morphology formed during oligomer-to-protofibril transition. To address this analytical gap, we establish an electrochemiluminescence (ECL) approach for monitoring of irregular oligomers with limited β-sheet content, which is based on the collisions between [Ru(bpy)₂dppz]²⁺-bound irregular oligomers and radical trin-propylamine (TPrA^·) that are electrochemically generated from TPrA oxidation in the diffusion layer at a carbon fiber microelectrode. The results demonstrate that the produced ECL intensity is related to the aggregate extent of [Ru(bpy)₂dppz]²⁺-bound irregular oligomer because of excessive TPrA^· radicals at the diffusion layer of the microelectrode. By integrating our electrochemical collision previously developed and this ECL method, we investigate the impact of heptafluorobutyric acid (HFBA) on early-stage amyloid fibril aggregation. The results demonstrate that HFBA accelerates the aggregation of early-stage amyloid fibrils. Molecular docking simulations further reveal that the accelerated aggregation of early-stage amyloid fibrils may be attributed to the hydrophobic and electronegative properties of HFBA, which lower the energy barrier for protein aggregation. This work not only provides crucial insights into the environmental factors in neurodegenerative pathogenesis but also offers prospective guidance for biosafety assessment and rational application of related compounds.