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Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy.
- Source :
-
Journal of Alzheimer's Disease . 2019, Vol. 72 Issue 2, p401-412. 12p. - Publication Year :
- 2019
-
Abstract
- <bold>Background: </bold>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.<bold>Objective: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *NUCLEOSIDE reverse transcriptase inhibitors
*AMYLOID plaque
*PHAGOCYTOSIS
*ALZHEIMER'S disease
*PROTEINS
*BIOCHEMISTRY
*CYTOKINES
*RESEARCH
*CELL culture
*REVERSE transcriptase inhibitors
*AUTOPHAGY
*RESEARCH methodology
*CELL receptors
*MACROPHAGES
*EVALUATION research
*MEDICAL cooperation
*PHENOMENOLOGY
*CELLULAR signal transduction
*MEMBRANE glycoproteins
*COMPARATIVE studies
*STAVUDINE
*GENES
*PEPTIDES
*PHARMACODYNAMICS
*CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 13872877
- Volume :
- 72
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Journal of Alzheimer's Disease
- Publication Type :
- Academic Journal
- Accession number :
- 139649601
- Full Text :
- https://doi.org/10.3233/JAD-181259