Nanoscale insights into the local structural rearrangements of amyloid-beta 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-beta aggregates and its primary aggregation. The molecular rearrangements and the spatial distribution of beta-sheets within individual aggregates were monitored at the nanoscale with infrared nanospectroscopy. We observed that bexarotene limits the parallel beta-sheets formation, known to be highly abundant in fibrils at later phases of the amyloid-beta aggregation composed of in-register cross-beta 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 beta-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-beta interaction contributes to a better understanding of the inhibition mechanism of the amyloid-beta aggregation by the small molecule drugs. However, our nanoscale findings need to meet in vivo research requiring different analytical approaches.

Automated summary

Through experimental and theoretical studies, we have revealed the influence of the anti-aggregation drug bexarotene on the secondary structure and primary aggregation of amyloid-beta aggregates. We observed that bexarotene limits the formation of parallel beta-sheets in the aggregates and slows down the aggregation process. Molecular dynamics simulations also provided insights into the interaction mechanism between bexarotene and the protein.