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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.

SUBMITTER: Yang T

PROVIDER: S-EPMC8905858 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

Yang Tao T Zhang Lei L Shang Yicun Y Zhu Zhenzhu Z Jin Suxing S Guo Zijian Z Wang Xiaoyong X

Chemical science 20220221 10

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. ...[more]

PMID: 35382471

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Project description:SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8±2.4%), MCI (32.8±5.4%) and preclinical AD (28.3±6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6±2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.

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

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

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