焦亡是一种程序性的细胞死亡方式，特征为依赖caspase1的激活，并伴有促炎因子释放。文献报道阿尔茨海默病（Alzheimer’s disease, AD）的主要病理改变——Aβ通过激活NLRP1诱导神经元焦亡。但是，AD的另一病理改变——tau蛋白磷酸化对焦亡有何影响目前仍不清楚。本课题组前期研究发现，侧脑室注射链脲佐菌素或者Forskolin大鼠脑内发生细胞焦亡的脑区与tau蛋白磷酸化的脑区具有一致性，抑制tau蛋白磷酸化，焦亡也被抑制。因此，我们提出假设“过度磷酸化tau蛋白通过激活炎症小体-caspase1途径，介导神经元焦亡”，并拟通过更具特异性的tau蛋白磷酸化模型（1）HEK293细胞瞬转人tau和GSK-3β；（2）大鼠侧脑室注射Wortmannin/GF-109203X；（3）P301S转基因小鼠；验证假设，并证明抑制NLRP1或caspase1可能是潜在的AD治疗靶点。

Pyroptosis is a kind of programmed cell death, which is dependent on caspase1 activation and leads to the release of pro-inflammatory cytokines. Literature reported that Aβ, a neuropathological hallmark of Alzheimer's disease (AD), could induce NLRP1-dependent neuronal pyroptosis. However, the effect of hyperphosphorylated tau, another hallmark of AD, on pyroptosis remains unclear. In our previous study, both of hyperphosphorylated tau and pyroptosis were found in the same brain region in intracerebroventricular(ICV) injection of Streptozotocin or Forskolin rats. Further, pyroptosis was attenuated by the inhibitor of hyperphosphorylated tau. Therefore, we suppose that hyperphosphorylated tau activates inflammasomes-caspase1 to induce neuronal pyroptosis. We use the following models: first, transiently transfected human tau and GSK-3β in HEK293 cells; second, combined ICV-Wortmannin and GF-109203X in rats; third, P301S transgenic mice, to test our hypothesis. Finally, provide support for the therapeutic potential target of NLRP1-caspase1 in AD.