Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer's Disease

Alzheimer's Disease ( AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazama-crocycle, which dramatically increases the binding affinity toward various amyloid beta (A beta) peptide aggregates, especially for soluble A beta oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the A beta oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the A beta species. Finally, exploiting the Cu2+-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble A beta aggregates and can thus be used to detect and regulate various A beta species in AD.

Automated summary

The development of the novel amphiphilic compound LS-4 significantly increases the binding affinity for various Aβ peptide aggregates, showing therapeutic potential for 5xFAD mice. The compound can penetrate the blood-brain barrier, reduce amyloid plaques and phosphorylated tau aggregates, and modulate microglia activation.