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bioRxiv · 10.1101/377945

Stavudine Reduces NLRP3-Inflammasome Activation and Upregulates Aβ-Autophagy

La Rosa, F.·Saresella, M.·Marventano, I.·Piancone, F.·Ripamonti, E.·Zoia, C. P.·Conti, E.·Ferrarese, C.·Clerici, M.
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Abstract

Alzheimers disease (AD) is associated with amyloid-beta (A{beta}) deposition and neuroinflammation, possibly driven by activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the assembly of the NLRP3 inflammasome; we analyzed whether stavudine (D4T), a prototypical NRTI, modulates A{beta}-mediated inflammasome activation; because neuroinflammation impairs A{beta} clearance by phagocytes, phagocytosis and autophagy were examined as well. THP-1-derived macrophages were stimulated in vitro with A{beta}42 alone or after LPS priming with/without D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR, phagocytosis and ASC-Speck by AmnisFlowSight, NLRP3-produced cytokines by ELISA, authophagy by P-ELISA evaluation of P-ERK and P-AKT. Results showed that IL1{beta}, IL18 and caspase-1 were increased whereas A{beta}-phagocytosis and TREM2 were reduced in LPS+A{beta}42-stimulated cells. D4T reduced NLRP3 assembly as well as IL18 and caspase-1 production, but not IL1{beta}, phagocytosis, and TREM2. P-AKT expression was augmented and P-ERK was reduced by D4T, suggesting a stimulatory effect on autophagy. D4T reduces NLRP3 inflammasome-associated inflammation, possibly restoring autophagy, in an in vitro model of AD; it will be interesting to verify its possibly beneficial effects in the clinical scenario.

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La Rosa, F., Saresella, M., Marventano, I., Piancone, F., Ripamonti, E., Zoia, C. P., Conti, E., Ferrarese, C., Clerici, M.. 2018-07-26. Stavudine Reduces NLRP3-Inflammasome Activation and Upregulates Aβ-Autophagy. https://doi.org/10.1101/377945

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