Amphiphilic Stilbene Derivatives Attenuate the Neurotoxicity of Soluble Aβ42 Oligomers by Controlling Their Interactions with Cell Membranes

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-β (Aβ) plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro binding experiments (i.e., fluorescence saturation assays) demonstrated that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit even higher binding affinity toward Aβ oligomers. These amphiphilic compounds can also label ex vivo Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. Molecular docking studies were performed to help understand the structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate Cu²⁺-Aβ induced toxicity in mouse neuroblastoma N2a via cell toxicity assays. In addition, confocal fluorescence imaging studies provided evidence that compounds ZY-15-MT and ZY-15-OMe can disrupt the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies suggest that developing compounds with amphiphilic properties that target Aβ oligomers can be an effective strategy for small molecule AD therapeutics.