Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity

Article abstract of DOI:10.1016/j.ejmech.2018.08.084

One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-β (Aβ) fibrils. Blocking Aβ self-assembly or disassembling Aβ aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aβ fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ～5.0 ? in length, which is close to the distance of adjacent β sheets in Aβ fibrils, showed good potency to inhibit Aβ(1–42) fibrillization. Furthermore, compound 2 effectively dissociated the Aβ(1–42) preformed fibrils. The cytotoxicity induced by Aβ(1–42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aβ transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aβ(1–40) were demonstrated by using electrospray ionization?traveling wave ion mobility?mass spectrometry, while molecular dynamic simulation was conducted to gain structural insights into the Aβ(1–40)?2 complex.