Concurrent suppression of Aβ aggregation and NLRP3 inflammasome activation for treating Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative illness accompanied by severe memory loss, cognitive disorders and impaired behavioral ability. Amyloid beta-peptide (A beta) aggregation and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome play crucial roles in the pathogenesis of AD. A beta plaques not only induce oxidative stress and impair neurons, but also activate the NLRP3 inflammasome, which releases inflammatory cytokine IL-1 beta to trigger neuroinflammation. A bifunctional molecule, 2-[2-(benzo[d]thiazol-2-yl)phenylamino]benzoic acid (BPBA), with both A beta-targeting and inflammasome-inhibiting capabilities was designed and synthesized. BPBA inhibited self- and Cu2+- or Zn2+-induced A beta aggregation, disaggregated the already formed A beta aggregates, and reduced the neurotoxicity of A beta aggregates; it also inhibited the activation of the NLRP3 inflammasome and reduced the release of IL-1 beta in vitro and vivo. Moreover, BPBA decreased the production of reactive oxygen species (ROS) and alleviated A beta-induced paralysis in transgenic C. elegans with the human A beta(42) gene. BPBA exerts an anti-AD effect mainly through dissolving A beta aggregates and inhibiting NLRP3 inflammasome activation synergistically.