AUTHOR=Atluri Venkata Subba Rao , Tiwari Sneham , Rodriguez Melisa , Kaushik Ajeet , Yndart Adriana , Kolishetti Nagesh , Yatham Mohan , Nair Madhavan 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 11 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2019.00342

DOI=10.3389/fnagi.2019.00342

ISSN=1663-4365

ABSTRACT=Alzheimer’s disease (AD) is a growing global threat to healthcare in the aging population. In the US alone, it is estimated that 1 in 9 persons over the age of 65 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-like receptor (NLRP3) and nuclear factor-kB (NF-kB) 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-kB 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 amyloid-beta (Aβ) production, NLRP3 mediated neuroinflammation and HDAC2 levels will have a translational significance in the prevention of neuroinflammation and associated neurodegeneration in AD patients.