Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice

Brain Behav Immun. 2017 Mar;61:306-316. doi: 10.1016/j.bbi.2016.12.014. Epub 2016 Dec 18.

Abstract

Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.

Keywords: APP/PS1 mice; Alzheimer’s disease; Caspase 1; Inflammasome; Interleukin-1β; Microglia; Neuroinflammation.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cognition / drug effects*
  • Disease Models, Animal
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Inflammasomes / drug effects*
  • Inflammasomes / metabolism
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Sulfones / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Heterocyclic Compounds, 4 or More Rings
  • Inflammasomes
  • MCC-950
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Presenilin-1
  • Sulfones