Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy

Francesca La Rosa, Marina Saresella, Ivana Marventano, Federica Piancone, Enrico Ripamonti, Nasser Al-Daghri, Chiara Bazzini, Chiara Paola Zoia, Elisa Conti, Carlo Ferrarese, Mario Clerici

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)401-412
Number of pages12
JournalJournal of Alzheimer's disease : JAD
Volume72
Issue number2
DOIs
Publication statusPublished - Nov 12 2019

Keywords

  • Alzheimer’s disease
  • amyloid-β phagocytosis
  • autophagy
  • cytokines
  • D4T
  • NLRP3-inflammasome

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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