Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model

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 inflammasomemediated 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.

Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

“…While it remains uncertain which of the mentioned mechanisms are pre-dominant, WA shows promise as a therapeutic intervention in diseases with chronically elevated levels of NF-κB levels such as Alzheimer [ 48 ], diabetes [ 36 ] and cystic fibrosis [ 35 ].…”

SVA insertion in X-linked Dystonia Parkinsonism alters histone H3 acetylation associated with TAF1 gene

“…Lastly, alterations in HAT and HDAC levels and activity have been described in several neurodegenerative diseases, such as HD [ 43 , 60 , 61 ], Alzheimer’s disease (AD) [ 62 , 63 ], Parkinson’s disease (PD) [ 64 , 65 ], amyotrophic lateral sclerosis (ALS) [ 66 , 67 ], and spinal muscle atrophy (SMA) [ 68 ]. Therefore, targeting HDACs and HATs has been suggested as potential therapeutic approach for the treatment of neurodegenerative diseases [ 69 – 71 ].…”

“…Therefore, targeting HDACs and HATs has been suggested as potential therapeutic approach for the treatment of neurodegenerative diseases [ 69 – 71 ]. For instance, targeting HDAC2 with the specific inhibitor mithramycin improved neuronal plasticity in cellular model of AD [ 63 ], while HDAC6 inhibition improved cognitive decline associated with HD [ 72 ], AD [ 73 ], tauopathy [ 74 ], and Charcot-Marie-Tooth disease [ 75 ]. Furthermore, three different HDAC inhibitor clinical trials were approved by the Food and Drug Administration (FDA) for treating neurodegenerative disorders, including sodium phenylbutyrate for the treatment of HD (Clinical Trial NCT00212316) [ 76 ] and ALS (Clinical Trial NCT00107770) [ 66 ], and valproic acid for the treatment of SMA (Clinical Trial NCT00227266) [ 68 ].…”

Fenamates as Potential Therapeutics for Neurodegenerative Disorders

“…MTM treatment reduced cerebral Aβ levels and plaque burden, inhibited APP processing, alleviated tau hyperphosphorylation, and inhibited phosphorylated CDK5 and GSK3β pathways in APPswe/PS1dE9 mice [ 90 ]. MTM treatment also upregulated synaptic plasticity gene expression in an AD model in vitro, and prolonged survival and improved motor performance in an HD mouse model [ 89 , 91 ]. Collectively, these reports support the SP1 hypothesis for neurodegenerative disease intervention.…”