Abstract
Our previous study indicated that inhibition of NLRP1-dependent pyroptosis could decrease intracerebroventricular (ICV) injection of a protein kinase A (PKA) agonist– or streptozotocin (STZ)-induced hyperphosphorylated tau. In this study, we used a glycogen synthase kinase-3β (GSK-3β) overactivation rat model to reconfirm our previous results. ICV injection of wortmannin (WT, a PI3K inhibitor) and GF-109203X (GFX, a PKC inhibitor) was used to induce overactivation of GSK-3β in rats. We injected NLRP1 siRNA together with WT/GFX to evaluate the effect of the inhibition of NLRP1-dependent neuronal pyroptosis on hyperphosphorylated tau. Our results indicated that ICV injection of NLRP1 siRNA prevented ICV-WT/GFX-induced neuronal death, further improving the spatial memory of the rats in the Morris water maze test. ICV injection of NLRP1 siRNA downregulated the expression of ASC, caspase-1, and GSDMD and the contents of IL-1β and IL-18 in rat brains. ICV injection of NLRP1 siRNA also decreased hyperphosphorylated tau and the activity of GSK-3β. Thus, these results support our previous study that NLRP1-dependent pyroptosis could enhance hyperphosphorylation of tau protein.
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Funding
This work was supported by the University Students’ Innovative Undertaking Program of Liaoning Province (No. S202010163029) and the National Natural Science Foundation of China (No. 81703494).
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Conceptualization: X. L., W. S., P. L. Methodology: X. L., Y. Y. Formal analysis and investigation: J. S., X. S., X. Y. Writing—original draft preparation: X. L., W. S., H. W. Writing—review and editing: P. L. Funding acquisition: P. L. Resources: P. L., L. Z. Supervision: P. L., L. Z.
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Liu, X., Song, W., Yu, Y. et al. Inhibition of NLRP1-Dependent Pyroptosis Prevents Glycogen Synthase Kinase-3β Overactivation–Induced Hyperphosphorylated Tau in Rats. Neurotox Res 40, 1163–1173 (2022). https://doi.org/10.1007/s12640-022-00554-y
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DOI: https://doi.org/10.1007/s12640-022-00554-y