Amphiphilic distyrylbenzene derivatives as potential therapeutic and imaging agents for the soluble amyloid‐β oligomers in Alzheimer’s disease

Abstract

AbstractBackgroundNew amphiphilic distyrylbenzene derivatives have been developed that target both the soluble Aβ oligomers and amyloid plaques in Alzheimer's disease (AD), as well as the extracellular p‐tau aggregates, Aβ‐mediated oxidative stress, and neuroinflammation.MethodWe have developed a novel amphiphilic distyrylbenzene derivative that exhibits high binding affinity for Aβ aggregates ‐ especially the Aβ oligomers, and a series of ex vivo and in vivo immunostaining and imaging studies were employed to probe the beneficial properties of this potential therapeutic agent.ResultUpon treatment of 5×FAD mice with an amphiphilic distyrylbenzene derivative, fluorescence imaging of the brain sections shows that this compound can easily penetrate the blood‐brain‐barrier and selectively bind to the Aβ oligomers, as confirmed by the colocalization with an Aβ oligomer‐specific antibody. Furthermore, when comparing the MFC‐treated mice vs. the vehicle‐treated mice, the total amount of Aβ species and the associated p‐tau aggregates was significantly decreased by up to 70%, along with a significant reduction in the amount of activated microglia.ConclusionThe amphiphilic distyrylbenzene compound reported herein can attenuate the formation of amyloid plaques and associated p‐tau aggregates, while also reducing the microglia‐mediated neuroinflammatory response, which is uncommon among the previously reported amyloid‐targeting chemical agents.