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.
Highlights
Alzheimer’s disease (AD), named as dementia is pathologically characterized by multiple factors, such as the presence of amyloid -protein (Aβ) and tau in the brain, especially in the hippocampus [1, 2]
To verify the toxicity of kainic acid (KA) in neurons, 10 mg/kg of KA were intraperitoneally injected to MAPT Tg mice, which were measured GSK3 truncation, nuclear factor (NF)- B phosphorylation, NLRP3, ASC and IL1β, as well as tau phosphorylation in the mice brains at 6, 12, 24, 48, 96 h
At the indicated time points after treatment with KA, GSK3 truncation, NF- B phosphorylation, NLRP3 and IL-1 expression, as well as tau phosphorylation were significantly elevated in the brains of the MAPT Tg mice (Figure 1A, 1B and Supplementary Figure 1A, 1B)
Summary
Alzheimer’s disease (AD), named as dementia is pathologically characterized by multiple factors, such as the presence of amyloid -protein (Aβ) and tau in the brain, especially in the hippocampus [1, 2]. The study by Heneka et al [3] suggested that the nucleotide binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) inflammasome plays a role in AD by demonstrating increased caspase-1 expression levels in brains with AD. The activation of caspase-1 results in secreting prowww.aging-us.com inflammatory cytokines including interleukin (IL)-1 , which is responsible for inducing a series of immunoresponses. Recruitment of procaspase-1 to inflammasome will induce the oligomerization and autocatalysis of caspase-1, leading to the release of active form of caspase-1 fragments and IL-1. The abovementioned mechanisms might potentially collaboratively contribute to the roles of the NLRP3 inflammasome in behavioral changes and cognitive deficiencies associated with AD
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