Background: Alzheimer's disease (AD) is associated with the accumulation of amyloid-β (Aβ) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly. Objective: We utilized an in vitro model reproducing the Aβ-driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aβ-mediated inflammasome activation and the ability of macrophages to eliminate Aβ via phagocytosis and autophagy. Methods: THP-1-derived macrophages were stimulated in vitro with Aβ42 or with Aβ42 after LPS-priming in the presence/absence of D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot. Results: IL-1β, IL-18, and caspase-1 were increased whereas Aβ phagocytosis and TREM2 were reduced in LPS+Aβ42-stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1β production and TREM2 expression. Notably, whereas D4T reduced Aβ phagocytosis, Aβ autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets. Conclusion: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aβ autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario.
Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy / F. La Rosa, M. Saresella, I. Marventano, F. Piancone, E. Ripamonti, N. Al-Daghri, C. Zoia, E. Conti, C. Ferrarese, M. Clerici. - In: JOURNAL OF ALZHEIMER'S DISEASE. - ISSN 1387-2877. - 72:2(2019), pp. 401-412.
|Titolo:||Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy|
|Parole Chiave:||Alzheimer's disease; amyloid-beta phagocytosis; autophagy; cytokines; D4T; NLRP3-inflammasome|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3233/JAD-181259|
|Appare nelle tipologie:||01 - Articolo su periodico|
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