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

Abstract

Alzheimer's disease (AD) is a neurodegenerative illness accompanied by severe memory loss, cognitive disorders and impaired behavioral ability. Amyloid β-peptide (Aβ) aggregation and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome play crucial roles in the pathogenesis of AD. Aβ plaques not only induce oxidative stress and impair neurons, but also activate the NLRP3 inflammasome, which releases inflammatory cytokine IL-1β to trigger neuroinflammation. A bifunctional molecule, 2-[2-(benzo[d]thiazol-2-yl)phenylamino]benzoic acid (BPBA), with both Aβ-targeting and inflammasome-inhibiting capabilities was designed and synthesized. BPBA inhibited self- and Cu2+- or Zn2+-induced Aβ aggregation, disaggregated the already formed Aβ aggregates, and reduced the neurotoxicity of Aβ aggregates; it also inhibited the activation of the NLRP3 inflammasome and reduced the release of IL-1β in vitro and vivo. Moreover, BPBA decreased the production of reactive oxygen species (ROS) and alleviated Aβ-induced paralysis in transgenic C. elegans with the human Aβ42 gene. BPBA exerts an anti-AD effect mainly through dissolving Aβ aggregates and inhibiting NLRP3 inflammasome activation synergistically.

• Authors: Tao Yang, Lei Zhang, Yicun Shang, Zhenzhu Zhu, Suxing Jin, Zijian Guo, Xiaoyong Wang
• Journal: Chemical science (Chem Sci) Vol. 13 Issue 10 Pg. 2971-2980 (Mar 09 2022) ISSN: 2041-6520 [Print] England
• PMID: 35382471 (Publication Type: Journal Article)
• Copyright: This journal is © The Royal Society of Chemistry.