Nanoscale insights into the local structural rearrangements of amyloid-β induced by bexarotene

A better understanding of the abnormal protein aggregation and the effect of anti-aggregation agents on the fibrillation pathways and the secondary structure of aggregates can determine strategies for the early treatment of dementia. Herein, we present a combination of experimental and theoretical studies providing new insights into the influence of the anti-aggregation drug bexarotene on the secondary structure of individual amyloid-β aggregates and its primary aggregation. The molecular rearrangements and the spatial distribution of β-sheets within individual aggregates were monitored at the nanoscale with infrared nanospectroscopy. We observed that bexarotene limits the parallel β-sheets formation, known to be highly abundant in fibrils at later phases of the amyloid-β aggregation composed of in-register cross-β structure. Moreover, we applied molecular dynamics to provide molecular-level insights into the investigated system. Both theoretical and experimental results revealed that bexarotene slows down the protein aggregation process via steric effects, largely prohibiting the antiparallel to parallel β-sheet rearrangement. We also found that bexarotene interacts not only via the single hydrogen bond formation with the peptide backbone but also with the amino acid side residue via a hydrophobic effect. The studied model of the drug-amyloid-β interaction contributes to a better understanding of the inhibition mechanism of the amyloid-β aggregation by the small molecule drugs. However, our nanoscale findings need to meet in vivo research requiring different analytical approaches. We report on the influence of aggregation suppressor on the secondary structure of amyloid-β species. The applied multimodal approach combining nanospectroscopic studies and molecular dynamics enabled to follow the interaction between the aggregating amyloid-β and a small molecule drug.