NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease.

Yulia K Komleva,Elena D Khilazheva,Olga L Lopatina,Alla B Salmina,Yana V Gorina,Anatoly Chernykh,Ilia V Potapenko,Anton N Shuvaev

doi:10.3390/ijms222111588

Abstract

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Methods: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. Results: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.

Highlights

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to dementia
We studied the formation of conditioned fear in the FC test in NLRP3KO mice after injection of soluble Aβ1-42 oligomers to interpret the effect of early changes in the brain
It can be said that injection of beta-oligomers for the purpose of inducing neuroinflammatory reactions in the brain of NLRP3KO mice did not lead to changes in the formation of the conditioned fear

Summary

Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to dementia It is pathologically characterized by neuronal loss, extracellular amyloid beta (Aβ) deposition and intracellular hyperphosphorylation of tau protein in the brain. This is manifested by a decrease in memory and learning, and by abnormal mental, emotional states and behaviors [1]. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder

Methods

Results

Conclusion