Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model
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...
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| Language: | English |
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Frontiers Media S.A.
2020-01-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnagi.2019.00342/full |
| _version_ | 1811206607546089472 |
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| author | Venkata Subba Rao Atluri Sneham Tiwari Melisa Rodriguez Ajeet Kaushik Adriana Yndart Nagesh Kolishetti Mohan Yatham Madhavan Nair |
| author_facet | Venkata Subba Rao Atluri Sneham Tiwari Melisa Rodriguez Ajeet Kaushik Adriana Yndart Nagesh Kolishetti Mohan Yatham Madhavan Nair |
| author_sort | Venkata Subba Rao Atluri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T03:50:05Z |
| format | Article |
| id | doaj.art-b745ef1735b44cc895693f646bb4a5c5 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-12T03:50:05Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-b745ef1735b44cc895693f646bb4a5c52022-12-22T03:49:00ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652020-01-011110.3389/fnagi.2019.00342491124Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro ModelVenkata Subba Rao Atluri0Sneham Tiwari1Melisa Rodriguez2Ajeet Kaushik3Adriana Yndart4Nagesh Kolishetti5Mohan Yatham6Madhavan Nair7Department of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesDepartment of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesDepartment of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesDivision of Sciences, Art, & Mathematics, Department of Natural Sciences, Florida Polytechnic University, Lakeland, FL, United StatesDepartment of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesDepartment of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesDepartment of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesDepartment of Immunology and Nano-Medicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United StatesAlzheimer’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.https://www.frontiersin.org/article/10.3389/fnagi.2019.00342/fullamyloid-betaAlzheimer’s diseaseinflammationwithaferin Acytokine release inhibitory drug 3mithramycin A |
| spellingShingle | Venkata Subba Rao Atluri Sneham Tiwari Melisa Rodriguez Ajeet Kaushik Adriana Yndart Nagesh Kolishetti Mohan Yatham Madhavan Nair Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model Frontiers in Aging Neuroscience amyloid-beta Alzheimer’s disease inflammation withaferin A cytokine release inhibitory drug 3 mithramycin A |
| title | Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model |
| title_full | Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model |
| title_fullStr | Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model |
| title_full_unstemmed | Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model |
| title_short | Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model |
| title_sort | inhibition of amyloid beta production associated neuroinflammation and histone deacetylase 2 mediated epigenetic modifications prevent neuropathology in alzheimer s disease in vitro model |
| topic | amyloid-beta Alzheimer’s disease inflammation withaferin A cytokine release inhibitory drug 3 mithramycin A |
| url | https://www.frontiersin.org/article/10.3389/fnagi.2019.00342/full |
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