Research Paper Volume 11, Issue 23 pp 10923—10938
Kainic acid hyperphosphorylates tau via inflammasome activation in MAPT transgenic mice
- 1 Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
- 2 Department of Hematology, Cancer Center, The First Hospital of Jilin University, Changchun 130021, China
- 3 Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm 141 86, Sweden
- 4 Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
Received: July 6, 2019 Accepted: November 17, 2019 Published: December 2, 2019
https://doi.org/10.18632/aging.102495How to Cite
Copyright © 2019 Zheng 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.
Abstract
The excitotoxicity induced by kainic acid (KA) is thought to contribute to the development of Alzheimer’s disease (AD); however, the mechanisms underlying this excitotoxicity remain unknown. In the current study, we investigated the dynamic changes in tau phosphorylation and their associations with the excitotoxicity induced by intraperitoneal injection of KA in the mouse brain. We found that KA-induced excitotoxicity led to sustained hyperphosphorylation of tau in MAPT transgenic (Tg) mice. By using cultured microglia and mouse brains, we showed that KA treatment specifically induced endoplasmic reticulum (ER) stress, which was characterized by activation of the major biomarkers of ER, such as ATF6, GRP78, and IRE1, and resulted in stimulation of inflammasomes. KA receptors (KARs), such as Girk1, were determined to be involved in this KA-induced ER stress. ER stress was also shown to activate inflammasomes by stimulating the expression of the two major components of inflammasomes, nucleotide binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) and nuclear factor (NF)-κB, and eventually causing the production of interleukin-1β (IL-1β). Inhibition of NLRP3 or NF-κB by Bay11-7082 resulted in reduction of KA-induced IL-1β production. Our results also revealed the positive effects of IL-1β on tau phosphorylation, which was blocked by Bay11-7082. Notably, the results indicate that Bay11-7082 acts against KA-induced neuronal degeneration, tau phosphorylation, and memory defects via inflammasomes, which further highlight the protective role of Bay11-7082 in KA-induced neuronal defects.