NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia

Neuropharmacology. 2020 Dec 1:180:108305. doi: 10.1016/j.neuropharm.2020.108305. Epub 2020 Sep 12.

Abstract

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated as a crucial component in both neurodegeneration and diabetes. However, the role of metabolic signalling pathways and the NLRP3 inflammasome in frontotemporal dementia remain largely elusive. We therefore investigated the effects of an NLRP3 inhibitor (MCC950) in a murine tau knock-in (PLB2TAU) model vs. wild-type (PLBWT) control mice. In male PLB2TAU mice (4 months at start of study), MCC950 treatment (20 mg/kg, for 12 weeks) improved insulin sensitivity and reduced circulating plasma insulin levels. Further molecular analysis suggested normalisation in insulin signalling pathways in both liver and muscle tissue. Treatment also resulted in improvements in inflammation and ER stress signalling, both peripherally and centrally, alongside a partial normalisation of phospho-tau levels. Overall, we provide evidence that MCC950 improved metabolic, inflammatory and frontotemporal dementia (FTD) relevant phenotypes in multiple tissues. NLRP3 inhibition may therefore offer a therapeutic approach to ameliorate FTD pathology.

Keywords: Dementia; Diabetes; ER stress; Inflammasome; Inflammation; Insulin; Knock-in; NLRP3; Transgenic; UPR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Frontotemporal Dementia / drug therapy*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Furans / pharmacology
  • Furans / therapeutic use*
  • Humans
  • Indenes / pharmacology
  • Indenes / therapeutic use*
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Insulin Resistance / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / genetics
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • tau Proteins / biosynthesis
  • tau Proteins / genetics

Substances

  • Furans
  • Indenes
  • MAPT protein, human
  • Nod-like receptor protein 3 inflammasome, mouse
  • Receptors, Cell Surface
  • Sulfonamides
  • tau Proteins
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide