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

doi:10.1016/j.neuropharm.2020.108305

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

University of Queensland

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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 language	English
Article number	108305
Number of pages	11
Journal	Neuropharmacology
Volume	180
Early online date	12 Sept 2020
DOIs	https://doi.org/10.1016/j.neuropharm.2020.108305
Publication status	Published - 1 Dec 2020

Bibliographical note

Acknowledgments:
This study was supported by ARUK project grant PG2017B-11 and ARUK summer scholarship funding from the Scottish ARUK network. The authors would like to thank Prof. Gernot Riedel for his support of the in vivo experimentation.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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

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. ",

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AU - Robertson, Avril

AU - Delibegovic, Mirela

AU - Platt, Bettina

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

Abstract

Bibliographical note

Keywords

UN SDGs

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