Kainic acid Induces production and aggregation of amyloid β-protein and memory deficits by activating inflammasomes in NLRP3- and NF-κB-stimulated pathways.

Yang Ruan,Xiang Qiu,Jie Zhu,Dong Dong,Yu-Dan Lv,Xiang-Yu Zheng,Xiu-Juan Wu

doi:10.18632/aging.102017

Abstract

Kainic acid (KA) treatment causes neuronal degeneration, which is a feature of Alzheimer’s disease (AD) symptoms such as amyloid β-protein production and memory deficits. Inflammasomes are known to be critical for the progression of AD. However, the underlying mechanism by which inflammasomes influence AD progression remains unknown. The present study investigated the damaging effect of KA on neurons by focusing on the inflammasome-mediated signaling pathways. Assessments using cultured microglia and mouse brains demonstrated that KA treatment specifically induced inflammasome activation. Mechanistic evaluations showed that KA activated two major components of inflammasomes, nucleotide binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) and nuclear factor (NF)-κB, which resulted in the production of interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). Inhibition of NLRP3 or NF-κB by Bay11-7082 caused a reduction in the KA-induced expression of interleukin (IL)-1β and BDNF. Moreover, knockdown of the expression of KA receptors (KARs) such as Grik1 and Grik3 induced suppression of NLRP3 and NF-κB, suggesting that KARs function upstream of NLRP3 and NF-κB to mediate the effects of KA on regulation of IL-1β and BDNF expression. Notably, IL-1β was shown to exert positive effects on the expression of BACE1, which is blocked by Bay11-7082. Overall, our results revealed that Bay11-7082 acts against KA-induced neuronal degeneration, amyloid β-protein (Aβ) deposition, and memory defects via inflammasomes and further highlighted the protective role of Bay11-7082 in KA-induced neuronal defects.

Highlights

Kainic acid (KA), an analogue of the excitotoxin glutamate, can cause seizures in rodents and subsequent degeneration of selective populations of neurons in the hippocampus via subcutaneous or intraperitoneal administration, which is a model for studying neurodegeneration in humans [1, 2]
At 12, 24, and 48 h after KA treatment, we observed a significant increase in the phosphorylation of nuclear factor (NF)-κB and the expression of NLRP3, IL-1β, and brain-derived neurotrophic factor (BDNF) in the brains of the respective APP23 mice (Figure 1A and 1B)
The results showed that KA started to induce the phosphorylation of NF-κB and the expression of NLRP3, IL-1β, and BDNF at 6 h, which was sustained to 48 h (Figure 1E, 1F)

Summary

Introduction

Kainic acid (KA), an analogue of the excitotoxin glutamate, can cause seizures in rodents and subsequent degeneration of selective populations of neurons in the hippocampus via subcutaneous or intraperitoneal administration, which is a model for studying neurodegeneration in humans [1, 2]. One example is the inflammatory cytokine IL-1β, the expression of which was known to be enhanced in KA-stimulated microglial cells, indicating the potential contribution of this cytokine in mediating the role of KA in the pathogenesis of AD [9]. Consistent with this speculation, KA was recently identified to be responsible for inducing learning and memory deficits in various neurodegenerative diseases [11]. Deficiencies in short-term and long-term spatial learning were both observed [12]

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Results

Conclusion