Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Neurotox Res. 2022 Oct;40(5):1163-1173. doi: 10.1007/s12640-022-00554-y. Epub 2022 Aug 11.
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。用 wortmannin（WT，PI3K 抑制剂）和 GF-109203X（GFX，PKC 抑制剂）脑室内注射诱导大鼠 GSK-3β过度激活。我们共同注射 NLRP1 siRNA 和 WT/GFX，以评估抑制 NLRP1 依赖性神经元细胞焦亡对过度磷酸化 tau 的影响。我们的结果表明，脑室内注射 NLRP1 siRNA 可防止 ICV-WT/GFX 诱导的神经元死亡，进一步改善了大鼠在 Morris 水迷宫测试中的空间记忆。脑室内注射 NLRP1 siRNA 下调了 ASC、caspase-1 和 GSDMD 的表达以及大鼠脑中 IL-1β 和 IL-18 的含量。脑室内注射 NLRP1 siRNA 还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。
