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

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.

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

“…23 Activation of the NLRP3 inflammasome in T2DM is associated with the development of brain IR which is involved in the degeneration of dopaminergic neurons in PD. 120 These findings indicate that T2DM-induced hyperglycaemia promotes the activation of the NLRP3 inflammasome with the propagation of systemic inflammation and the development of neuroinflammation and subsequent degeneration of dopaminergic neurons in the SN (Figure 8).…”

“…These mediators can cross BBB causing the activation of the NLRP3 inflammasome and the deposition of α‐synuclein with the development of PD 23 . Activation of the NLRP3 inflammasome in T2DM is associated with the development of brain IR which is involved in the degeneration of dopaminergic neurons in PD 120 …”

Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration

“…62 However, NLR family pyrin domain containing 3 (NLRP3) knockout protects mice from brain insulin resistance induced by beta amyloid injection. 63 The liver's central role in metabolism and glucose homeostasis confers the ability to regulate several systemic conditions, including inflammation. 64 Within the liver, resident macrophages (KCs) shift to an M1 proinflammatory macrophage phenotype during the transition from simple steatosis to NASH, increasing proinflammatory cytokine production and systemic inflammation correlating with the severity of steatosis and NASH.…”

Physiological and Pathological Remodeling of Cerebral Microvessels

“…Control of inflammation and insulin resistance achieved by the suppression of inflammasome formation is a way to prevent vascular cognitive impairments [ 175 ]. Other approaches to suppressing aberrant angiogenesis and microvessel regression in brain diseases are based on the application of pharmacological inhibitors of hypoxia-driven events, BMEC apoptosis, extracellular traps of neutrophils, canonical/non-canonical Wnt/β-catenin signaling pathways, and mechanisms contributing to vascular pathology in brain diseases [ 176 , 177 , 178 , 179 ] ( Figure 2 ). However, it should always be taken into consideration that physiological signaling pathways might be completely deregulated in the brain pathology, thereby leading to unexpected outcomes of the proposed treatments.…”