Lychee seed polyphenol inhibits Aβ-induced activation of NLRP3 inflammasome via the LRP1/AMPK mediated autophagy induction

Biomed Pharmacother. 2020 Oct:130:110575. doi: 10.1016/j.biopha.2020.110575. Epub 2020 Aug 5.

Abstract

Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer's disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.

Keywords: 4',6-Diamidino-2-phenylindole (PubChem CID: 2954); AICAR (PubChem CID: 266934); Alzheimer's disease; Autophagy; Aβ(1-42); Bafilomycin A1 (PubChem CID: 6436223); Compound C (PubChem CID: 11524144); LRP1/AMPK; LY294002 (PubChem CID: 3973); Lychee seed polyphenol; NLRP3 inflammasome; Rapamycin (PubChem CID: 5284616); SBI-0206965 (PubChem CID: 92044402); Thiazolyl blue (PubChem CID: 64965).

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides*
  • Animals
  • Autophagy / drug effects
  • Cell Line
  • Disease Models, Animal
  • Inflammasomes / antagonists & inhibitors*
  • Inflammasomes / metabolism
  • Litchi*
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Male
  • Maze Learning / drug effects
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments*
  • Polyphenols / pharmacology*
  • RNA, Small Interfering
  • Rats
  • Seeds

Substances

  • Amyloid beta-Peptides
  • Inflammasomes
  • Low Density Lipoprotein Receptor-Related Protein-1
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neuroprotective Agents
  • Peptide Fragments
  • Polyphenols
  • RNA, Small Interfering
  • amyloid beta-protein (1-42)
  • AMP-Activated Protein Kinases