Tu, L.-H.L.-H.TuTseng, N.-H.N.-H.TsengTsai, Y.-R.Y.-R.TsaiLin, T.-W.T.-W.LinLo, Y.-W.Y.-W.LoCharng, J.-L.J.-L.CharngHsu, H.-T.H.-T.HsuChen, Y.-S.Y.-S.ChenChen, R.-J.R.-J.ChenWu, Y.-T.Y.-T.WuChan, Y.-T.Y.-T.ChanChen, C.-S.C.-S.ChenFang, J.-M.J.-M.FangChen, Yun-RuYun-RuChen2019-06-282019-06-282018https://www.scopus.com/inward/record.uri?eid=2-s2.0-85053414613&doi=10.1016%2fj.ejmech.2018.08.084&partnerID=40&md5=65895164977057b0d67699b6fc2cb903https://scholars.lib.ntu.edu.tw/handle/123456789/411903One 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. ? 2018 Elsevier Masson SAS[SDGs]SDG3[SDGs]SDG6amide; amyloid beta protein[1-40]; amyloid beta protein[1-42]; caffeic acid; caffeic acid derivative; curcumin; lonidamine; amide; amyloid beta protein; amyloid beta-protein (1-42); caffeic acid; caffeic acid derivative; peptide fragment; Article; beta sheet; Caenorhabditis elegans; controlled study; drug binding; drug design; drug potency; drug synthesis; electrospray; human; human cell; ion mobility spectrometry-mass spectrometry; neuroprotection; neurotoxicity; nonhuman; paralysis; phenotype; SH-SY5Y cell line; stoichiometry; Alzheimer disease; animal; chemistry; drug effect; metabolism; molecular model; protein multimerization; ultrastructure; Alzheimer Disease; Amides; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Caffeic Acids; Humans; Models, Molecular; Peptide Fragments; Protein Multimerizationjournal article10.1016/j.ejmech.2018.08.0842-s2.0-85053414613