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

Tao Yang,Zijian Guo,Suxing Jin,Xiaoyong Wang,Zhenzhu Zhu,Yicun Shang,Lei Zhang

doi:10.1039/d1sc06071f

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.

Highlights

Alzheimer's disease (AD) is a common form of dementia characterized by the accumulation of extracellular amyloid bpeptide (Ab) plaques, neuroin ammation and neuronal cell death in the brain.[1]
The Ab cascade hypothesis is the most prevalent supposition about the pathogenesis of AD, which suggests that Ab deposits play a vital role in initiating the disease.[5,6]
The design of BPBA is based on the structures of benzothiazole and o-aminobenzoic acid; the former is a potential Ab-targeting group that has a speci c affinity for Ab aggregates rich in bsheet structures, and the latter is an analogue of mefenamic acid, which is a known inhibitor of the NLRP3 in ammasome.[32]

Summary

Introduction

Aducanumab is the rst anti-AD drug based on the Ab cascade hypothesis, though its efficacy is inconclusive.[8]. Various inhibitors of the in ammasome have been reported,[23] such as OLT1177,19,24 CY-09,25 tranilast,[26] oridonin,[27] benzenesulfonamide analogues,[28] sulphonamides (CRIDI, MCC950),[29,30,31] and non-steroidal anti-in ammatory drugs (NSAIDs).[12,32] More inhibitors are targeted to Ab aggregation;[33,34,35] inhibitors that emphasize both Ab aggregation and in ammasome are rare. A series of experiments demonstrate that BPBA remarkably inhibits the self- and metalinduced Ab aggregation, reduces the level of in ammatory cytokine IL-1b, restrains the activation of caspase-1 in vitro, and alleviates the formation of Ab oligomers and plaques as well as the Ab-associated toxicity in vivo

Results and discussion

Inhibition of Ab aggregation

Morphological alteration of Ab

In uence on the hydrophobicity of Ab

Effect of BPBA on nerve cells and Ab toxicity

Reduction of Ab and IL-1b in AD mice

Conclusion