RESUMO
Alzheimer's disease (AD) is a neurodegenerative illness accompanied by severe memory loss, cognitive disorders and impaired behavioral ability. Amyloid ß-peptide (Aß) aggregation and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome play crucial roles in the pathogenesis of AD. Aß plaques not only induce oxidative stress and impair neurons, but also activate the NLRP3 inflammasome, which releases inflammatory cytokine IL-1ß to trigger neuroinflammation. A bifunctional molecule, 2-[2-(benzo[d]thiazol-2-yl)phenylamino]benzoic acid (BPBA), with both Aß-targeting and inflammasome-inhibiting capabilities was designed and synthesized. BPBA inhibited self- and Cu2+- or Zn2+-induced Aß aggregation, disaggregated the already formed Aß aggregates, and reduced the neurotoxicity of Aß aggregates; it also inhibited the activation of the NLRP3 inflammasome and reduced the release of IL-1ß in vitro and vivo. Moreover, BPBA decreased the production of reactive oxygen species (ROS) and alleviated Aß-induced paralysis in transgenic C. elegans with the human Aß42 gene. BPBA exerts an anti-AD effect mainly through dissolving Aß aggregates and inhibiting NLRP3 inflammasome activation synergistically.