Journal
AGING-US
Volume 11, Issue 23, Pages 10923-10938Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102495
Keywords
kainic acid; NLRP3; NF-kappa B; interleukin-1 beta; tau
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Funding
- National Natural Science Foundation of China [81873812, 81471216, 81671186, 81671177, 31600820]
- Education Department of Jilin Province [JJKH20190035KJ]
- Norman Bethune Program of Jilin University [2015419, 2015421]
- Health and Family Planning Commission of Jilin Province of China [2014Q028]
- First Hospital of Jilin University [JDYY52014019]
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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 KAinduced 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)-kappa B, and eventually causing the production of interleukin-1 beta (IL-1 beta). Inhibition of NLRP3 or NF-kappa B by Bay11-7082 resulted in reduction of KA-induced IL-1 beta production. Our results also revealed the positive effects of IL-1 beta 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.
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