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

Claire Hull, Ruta Dekeryte, Heather Buchanan, Sarah Kamli-Salino, Avril Robertson, Mirela Delibegovic, Bettina Platt* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

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.
Original languageEnglish
Article number108305
Pages (from-to)108305
JournalNeuropharmacology
Volume180
Early online date12 Sep 2020
DOIs
Publication statusE-pub ahead of print - 12 Sep 2020

Keywords

  • Transgenic
  • Knock-in
  • Diabetes
  • Insulin
  • Dementia
  • NLRP3
  • Inflammasome
  • ER stress
  • UPR
  • Inflammation

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