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Article

Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease

1
IRCCS Fondazione Don C. Gnocchi, ONLUS, 20148 Milan, Italy
2
Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
3
Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy
4
Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Concetta Saponaro, Raffaella Soleti, Simona De Summa and Antonia Cianciulli
Pharmaceuticals 2021, 14(11), 1187; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111187
Received: 30 September 2021 / Revised: 17 November 2021 / Accepted: 18 November 2021 / Published: 20 November 2021
Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pathologies including Alzheimer’s Disease (AD). MicroRNAs (miR-NAs) target the 3′UTR region of NLRP3, preventing the activation of the inflammasome and inhibiting cytokine production. Because Stavudine (D4T), an antiretroviral drug, was recently shown to reduce inflammasome activation, we verified whether its effect is mediated by miR-7-5p, miR-22-3p, miR-30e-5p and miR-223-3p: miRNAs that bind the NLRP3-mRNA-UTR region and interfere with protein translation, reducing NLRP3 activation. Peripheral blood mononuclear cells (PBMCs) of twenty AD patients and ten sex-matched Healthy Controls (HC) were stimulated with Lipopolysaccharides (LPS)+Amyloid-beta (Aβ42) in the absence/presence of D4T. Expression of genes within the inflammasome complex and of miRNAs was evaluated by RT-PCR; cytokines and caspase-1 production was measured by ELISA. Results have shown that: NLRP3, ASC, IL-1β and IL-18 expression, as well as IL-18, IL-1β and caspase-1 production, were significantly augmented (p < 0.05) in LPS+Aβ42-stimulated PBMCs of AD patients compared to HC. D4T reduced the expression of inflammasome genes and cytokine production (p < 0.005). miR-7-5p and miR-223-3p expression was significantly increased in LPS+Aβ42-stimulated PBMCs of AD patients (p < 0.05), and it was reduced by D4T in AD alone. In conclusion: miR-223-3p and mir-7-5p expression is increased in AD, but this does not result in down-regulation of NLRP3 inflammasome expression and of IL-1β and IL-18 production. D4T increased miRNA expression in HC but had an opposite effect in AD, suggesting that miRNA regulatory mechanisms are altered in AD. View Full-Text
Keywords: Alzheimer’s disease; D4T; miRNAs; NLRP3 inflammasome Alzheimer’s disease; D4T; miRNAs; NLRP3 inflammasome
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MDPI and ACS Style

La Rosa, F.; Mancuso, R.; Agostini, S.; Piancone, F.; Marventano, I.; Saresella, M.; Hernis, A.; Fenoglio, C.; Galimberti, D.; Scarpini, E.; Clerici, M. Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease. Pharmaceuticals 2021, 14, 1187. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111187

AMA Style

La Rosa F, Mancuso R, Agostini S, Piancone F, Marventano I, Saresella M, Hernis A, Fenoglio C, Galimberti D, Scarpini E, Clerici M. Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease. Pharmaceuticals. 2021; 14(11):1187. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111187

Chicago/Turabian Style

La Rosa, Francesca, Roberta Mancuso, Simone Agostini, Federica Piancone, Ivana Marventano, Marina Saresella, Ambra Hernis, Chiara Fenoglio, Daniela Galimberti, Elio Scarpini, and Mario Clerici. 2021. "Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease" Pharmaceuticals 14, no. 11: 1187. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111187

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