Research Paper Volume 11, Issue 11 pp 3795—3810
Kainic acid Induces production and aggregation of amyloid β-protein and memory deficits by activating inflammasomes in NLRP3- and NF-κB-stimulated pathways
- 1 Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
- 2 Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
- 3 Department of Radiology, The First Hospital of Jilin University, Changchun 130021, China
- 4 Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm 141 86, Sweden
received: February 1, 2019 ; accepted: June 3, 2019 ; published: June 10, 2019 ;https://doi.org/10.18632/aging.102017
How to Cite
Copyright: Ruan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.