Amphiphilic stilbene derivatives attenuate the neurotoxicity of soluble Aβ42 oligomers by controlling their interactions with cell membranes

The misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer's disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-beta (A beta) peptide plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro fluorescence binding assays demonstrate that these amphiphilic compounds show high binding affinity to both A beta plaques and oligomers, and six of them exhibit selective binding toward A beta oligomers. These amphiphilic compounds can also label the A beta species in the brain sections of transgenic AD mice, as shown by immunostaining with an A beta antibody. Molecular docking studies were performed to obtain structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate the Cu2+-A beta induced toxicity in cell viability assays. In addition, confocal fluorescence imaging studies provide evidence that two compounds, ZY-15-MT and ZY-15-OMe, can disrupt the interactions between A beta oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies strongly suggest that developing compounds with amphiphilic properties that target A beta oligomers and modulate the A beta oligomer-cell membrane interactions can be an effective strategy for the development of small molecule AD therapeutics.

Automated summary

This study developed twelve small molecule compounds with different amphiphilic properties, which showed high binding affinity to the hallmark Aβ plaques and oligomers of Alzheimer's disease. These compounds also exhibited the ability to alleviate Cu2+-Aβ induced toxicity and disrupt the interactions between Aβ oligomers and cell membranes.