Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, PR China.
Biomed Pharmacother. 2020 Jan;121:109618. doi: 10.1016/j.biopha.2019.109618. Epub 2019 Nov 12.
Amyloid-β (Aβ) activating the pyroptotic cell pathway has been reported to act as a component in the progression of Alzheimer's disease (AD). As another major pathophysiological protein process in AD, the abnormal hyperphosphorylation of tau proteins exerts neurotoxic effects through a variety of mechanisms. However, data describing the relationship between hyperphosphorylated tau proteins and pyroptosis are very scarce. In this study, we used two hyperphosphorylated tau models, intracerebroventricular (ICV) forskolin (FSK, a PKA activator) rat model and ICV-streptozotocin (STZ) rat model; also, FSK and STZ treated PC12 cells as in vitro models to test the relationship between hyperphosphorylated tau proteins and pyroptosis. We found that FSK and STZ significantly increased the hyperphosphorylated tau level, pyroptosis-related protein in PC12 cell and rats' brain, and inhibited the activity of caspase-1 by caspase-1 inhibitor, caspase-1 siRNA, or incubated with Interleukin(IL)-1β/IL-18 neutralizing antibody could notably alleviate the FSK and STZ induced PC12 cells damage and improve the cognitive disorder in ICV-FSK and ICV-STZ rats. Suppressed the level of hyperphosphorylated tau by LiCl also significantly decreased caspase-1 activity and the content of inflammatory cytokines in FSK or STZ treated PC12 cells. In summary, our results demonstrated that inflammasomes mediated pyroptosis at least one underlying pathogenic mechanism for the neurotoxicity induced by hyperphosphorylated tau in PC12 cells and dementia rats. IL-1β and IL-18, the downstream of caspase-1, in turn increased hyperphosphorylated tau while spreading neuroinflammation.
淀粉样蛋白-β（Aβ）激活细胞焦亡途径已被报道作为阿尔茨海默病（AD）进展的组成部分。作为 AD 中另一个主要的病理生理蛋白过程，tau 蛋白的异常过度磷酸化通过多种机制发挥神经毒性作用。然而，描述过度磷酸化 tau 蛋白与细胞焦亡之间关系的数据非常稀缺。在这项研究中，我们使用了两种过度磷酸化 tau 模型，即侧脑室（ICV）福斯克林（FSK，一种 PKA 激活剂）大鼠模型和 ICV-链脲佐菌素（STZ）大鼠模型；此外，FSK 和 STZ 处理的 PC12 细胞作为体外模型，以测试过度磷酸化 tau 蛋白与细胞焦亡之间的关系。我们发现，FSK 和 STZ 显著增加了 PC12 细胞和大鼠大脑中过度磷酸化 tau 水平、细胞焦亡相关蛋白，并用 caspase-1 抑制剂、caspase-1 siRNA 孵育或用白细胞介素（IL）-1β/IL-18 中和抗体处理可显著减轻 FSK 和 STZ 诱导的 PC12 细胞损伤，并改善 ICV-FSK 和 ICV-STZ 大鼠的认知障碍。LiCl 抑制过度磷酸化 tau 水平也显著降低了 FSK 或 STZ 处理的 PC12 细胞中 caspase-1 的活性和炎症细胞因子的含量。总之，我们的结果表明，炎性小体介导的细胞焦亡是过度磷酸化 tau 诱导的 PC12 细胞和痴呆大鼠神经毒性的至少一种潜在发病机制。caspase-1 的下游产物白细胞介素-1β和白细胞介素-18 反过来又增加了过度磷酸化 tau，同时扩大了神经炎症。
