Insulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive dysfunction, but its mechanism is not fully clarified. The aim of the study was to reveal whether IGF-1 treated cognitive dysfunction by improving tau pathology and neuronal pyroptosis in high-fat diet mice. During in vitro experiment, C57BL/6J mice were fed with high-fat diet, and were treated with PEG-IGF-1, IGF-1 receptor blocker AXL1717, HO-1 blocker Znpp IX or their combinations. Cognitive function was evaluated using Morris water maze. Expression of Nrf2, HO-1, p-tau, NLRP3, caspase-1 and IL-1β in hippocampus was determined using western blotting. Pyroptosis rate in hippocampus was measured using flow cytometry. During in vivo experiment, HN-h cells were treated with palmitic acid, pyroptosis blocker nonecrosulfonamide or their combinations. The expression of the proteins and rate of pyroptosis were also measured using western blotting and flow cytometry. During in vitro experiment, high-fat diet mice showed cognitive dysfunction, significant hyperphosphorylation of tau protein and neuronal pyroptosis in hippocampus compared with the sham mice. After exogenous IGF-1 treatment, these abnormalities were reversed and Nrf2/HO-1 signaling pathway was activated. Inhibition of the signaling pathway using AXL1717 or Znpp IX re-deteriorated cognitive function, tau pathology and neuronal pyroptosis in hippocampus. During in vivo experiment, inhibition of pyroptosis using nonecrosulfonamide improved tau pathology in palmitic acid-treated HN-h cells. Exogenous IGF-1 improved tau pathology induced by high-fat diet through inhibition of neuronal pyroptosis and activation of Nrf2/HO-1 signaling pathway.

胰岛素样生长因子-1 (IGF-1) 可改善肥胖引起的认知功能障碍，但其机制尚未完全阐明。该研究的目的是揭示 IGF-1 是否通过改善高脂饮食小鼠的 tau 病理和神经元焦亡来治疗认知功能障碍。在体外实验中，C57BL/6J小鼠喂以高脂饮食，并给予PEG-IGF-1、IGF-1受体阻滞剂AXL1717、HO-1阻滞剂Znpp IX或它们的组合治疗。使用莫里斯水迷宫评估认知功能。Nrf2、HO-1、p的表达使用蛋白质印迹测定海马中的 -tau、NLRP3、caspase-1 和 IL-1β。使用流式细胞术测量海马中的焦亡率。在体内实验中，HN-h 细胞用棕榈酸、焦亡阻滞剂非克罗磺胺或其组合处理。还使用蛋白质印迹和流式细胞术测量蛋白质的表达和细胞焦亡率。在体外实验中，高脂饮食小鼠与假小鼠相比，表现出认知功能障碍、tau蛋白显着过度磷酸化和海马神经元焦亡。外源性IGF-1处理后，这些异常被逆转，Nrf2/HO-1信号通路被激活。使用 AXL1717 或 Znpp IX 抑制信号通路会再次恶化海马中的认知功能、tau 病理学和神经元焦亡。在体内实验中，使用非克罗磺胺抑制细胞焦亡改善了棕榈酸处理的 HN-h 细胞的 tau 病理学。外源性 IGF-1 通过抑制神经元细胞焦亡和激活 Nrf2/HO-1 信号通路改善高脂饮食诱导的 tau 病理。