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.

我们之前的研究表明，抑制 NLRP1 依赖性细胞焦亡可以减少脑室内 (ICV) 注射蛋白激酶 A (PKA) 激动剂或链脲佐菌素 (STZ) 诱导的过度磷酸化 tau。在这项研究中，我们使用糖原合酶激酶 3β (GSK-3β) 过度激活大鼠模型来重新确认我们之前的结果。ICV 注射渥曼青霉素（WT，一种 PI3K 抑制剂）和 GF-109203X（GFX，一种 PKC 抑制剂）用于诱导大鼠 GSK-3β 的过度活化。我们将 NLRP1 siRNA 与 WT/GFX 一起注射以评估抑制 NLRP1 依赖性神经元焦亡对过度磷酸化 tau 的影响。我们的结果表明，ICV 注射 NLRP1 siRNA 可防止 ICV-WT/GFX 诱导的神经元死亡，进一步改善 Morris 水迷宫试验中大鼠的空间记忆。ICV 注射 NLRP1 siRNA 下调大鼠脑中 ASC、caspase-1 和 GSDMD 的表达以及 IL-1β 和 IL-18 的含量。ICV 注射 NLRP1 siRNA 也降低了过度磷酸化的 tau 和 GSK-3β 的活性。因此，这些结果支持我们之前的研究，即 NLRP1 依赖性细胞焦亡可以增强 tau 蛋白的过度磷酸化。