Formation of Dynamic Soluble Surfactant-induced Amyloid β Peptide Aggregation Intermediates

Intermediate amyloidogenic states along the amyloid beta peptide (A beta) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during A beta aggregation, we here investigate surfactant-induced A beta aggregation. This process leads to co-aggregates featuring a beta-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in A beta in a concentration-dependent manner, from predominantly random coil at low surfactant concentration, via beta-structure to the fully formed beta-helical state at high surfactant concentration. The beta-rich state is the most aggregation-prone as monitored by thioflavin T fluorescence. Small angle x-ray scattering reveals initial globular structures of surfactant-A beta co-aggregated oligomers and formation of elongated fibrils during a slow aggregation process. Alongside this slow (minutes to hours time scale) fibrillation process, much faster dynamic exchange (k(ex) similar to 1100 s(-1)) takes place between free and co-aggregate-bound peptide. The two hydrophobic segments of the peptide are directly involved in the chemical exchange and interact with the hydrophobic part of the co-aggregates. Our findings suggest a model for surfactant-induced aggregation where free peptide and surfactant initially co-aggregate to dynamic globular oligomers and eventually form elongated fibrils. When interacting with beta-structure promoting substances, such as surfactants, A beta is kinetically driven toward an aggregation-prone state.