TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer's disease

Int Immunopharmacol. 2018 Jan:54:78-85. doi: 10.1016/j.intimp.2017.10.024. Epub 2017 Nov 4.

Abstract

Recent studies have shown that neuroinflammation plays an important role in Alzheimer's disease (AD). Microglial cells are responsible for the phagocytosis of Amyloid-β (Aβ). However, it has been demonstrated that in AD patients the efficiency of phagocytosis decreases due to proinflammatory cytokines, such as Interleukin-1β (IL-1β), which is produced through the activation of NLRP3 inflammasome. In this study, we aimed at deciphering the mechanism underlying the NLRP3 activation. The results showed that Aβ induces an increase in the level of reactive oxygen species (ROS). According to this study, ROS produced from both mitochondria and NADPH oxidase was responsible for NLRP3 activation. In addition, it was observed that this high level of ROS activated the transient receptor potential melastatin 2 (TRPM2) channel, which causes an increase in the level of intracellular calcium. The results demonstrated that in the absence of intracellular calcium, caspase-1 cannot be activated and therefore the level of IL-1β decreases. Altogether, our findings supported the role of TRPM2 channel in ROS-induced NLRP3 activation in microglial cells through the exposure to Aβ.

Keywords: Alzheimer's disease; Amyloid-β; NLRP3 inflammasome; Reactive oxygen species; TRPM2 channel.

MeSH terms

  • Alzheimer Disease / immunology*
  • Amyloid beta-Peptides / immunology*
  • Animals
  • Calcium / metabolism
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Cytophagocytosis
  • Disease Models, Animal
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Mitochondria / metabolism*
  • Neurogenic Inflammation / immunology*
  • Neuroglia / physiology*
  • Peptide Fragments / immunology*
  • Rats
  • Rats, Inbred Strains
  • Reactive Oxygen Species / metabolism
  • TRPM Cation Channels / metabolism*

Substances

  • Amyloid beta-Peptides
  • Inflammasomes
  • Interleukin-1beta
  • Peptide Fragments
  • Reactive Oxygen Species
  • TRPM Cation Channels
  • Trpm2 protein, rat
  • amyloid beta-protein (1-42)
  • Caspase 1
  • Calcium