Abstract

Alzheimer’s disease (AD) is a growing global threat to healthcare in the aging population. In the USA alone, it is estimated that one in nine persons over the age of 65 years is living with AD. The pathology is marked by the accumulation of amyloid-beta (Aβ) deposition in the brain, which is further enhanced by the neuroinflammatory process. Nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are the major neuroinflammatory pathways that intensify AD pathogenesis. Histone deacetylase 2 (HDAC2)-mediated epigenetic mechanisms play a major role in the genesis and neuropathology of AD. Therefore, therapeutic drugs, which can target Aβ production, NLRP3 activation, and HDAC2 levels, may play a major role in reducing Aβ levels and the prevention of associated neuropathology of AD. In this study, we demonstrate that withaferin A (WA), an extract from Withania somnifera plant, significantly inhibits the Aβ production and NF-κB associated neuroinflammatory molecules’ gene expression. Furthermore, we demonstrate that cytokine release inhibitory drug 3 (CRID3), an inhibitor of NLRP3, significantly prevents inflammasome-mediated gene expression in our in vitro AD model system. We have also observed that mithramycin A (MTM), an HDAC2 inhibitor, significantly upregulated the synaptic plasticity gene expression and downregulated HDAC2 in SH-SY5Y cells overexpressing amyloid precursor protein (SH-APP cells). Therefore, the introduction of these agents targeting Aβ production, NLRP3-mediated neuroinflammation, and HDAC2 levels will have a translational significance in the prevention of neuroinflammation and associated neurodegeneration in AD patients.

Highlights

  • Alzheimer’s disease (AD), the most prevailing cause of dementia in the world, affects nearly 5.7 million Americans

  • For the first time, we have explored the use of cytokine release inhibitory drug 3 (CRID3) in inhibiting inflammasome-mediated neuroinflammation in an in vitro AD model (SH-APP cells cocultured with microglial CHME5 cells)

  • We studied the effect of withaferin A (WA) on Aβ production by staining the cells with Congo red (CR) stain

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Summary

Introduction

Alzheimer’s disease (AD), the most prevailing cause of dementia in the world, affects nearly 5.7 million Americans. In AD, microglia are stimulated by binding to soluble Aβ oligomers and Aβ fibrils via cell-surface receptors, which induce inflammatory reaction by the activation of nucleotidebinding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasomes and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway resulting in proinflammatory cytokines and chemokines release (Bonaiuto et al, 1997; Agostinho et al, 2010; Cameron and Landreth, 2010; Mandrekar-Colucci and Landreth, 2010; Heneka et al, 2013). In AD patients, activation of NLRP3 and NF-κB cascades inhibit the Aβ phagocytosis by microglia leading to enhanced deposition of Aβ fibrils, thereby creating a selfperpetuating loop, which further induces the neuroinflammation (Heneka et al, 2013)

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