Jia Jinjing, Sheng Zixuan, Zhang Yuqian, Guo Lunxi, Chen Zhuo'er, Zhu Dongsheng, Zeng Xiansi, Liu Hongjun
Research Center of Neuroscience, Jiaxing University Medical College, Jiaxing, 314001, China.
Department of Physiology, Jiaxing University Medical College, Jiaxing, 314001, China.
Sci Rep. 2025 May 13;15(1):16551. doi: 10.1038/s41598-025-01636-5.
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by memory loss. Our recent study has demonstrated that thioredoxin-1 (Trx-1) could protect neurons via repressing NLRP1‑mediated neuronal pyroptosis in AD models. However, whether Trx-1 could inhibit NLRP3 activation is largely unknown. Here, we found that AAV-mediated Trx-1 overexpression significantly inhibited NLRP3-mediated pyroptosis in the hippocampus of APP/PS1 mice. A mouse hippocampal neuron HT22 cell line overexpressing Trx-1 was successfully obtained through lentivirus transfection. Further study showed that Trx-1 overexpression protected HT22 cells against the neurocytotoxicity of Aβ. Consistently with the results of in vivo experiments, overexpression of Trx-1 remarkedly inhibited the activation of NLRP3. In the contrary, knockdown of Trx-1 by siRNA transfection further aggravated the activation of NLRP3. Mechanistically, Trx-1 overexpression significantly inhibited the increase of thioredoxin-interacting protein (TXNIP) in in vivo and in vitro and weakened the interaction between TXNIP and NLRP3. Taken together, Trx-1 inhibits NLRP3-mediated pyroptosis by regulating TXNIP expression and its interaction with NLRP3 in AD models.
阿尔茨海默病（AD）是最常见的以记忆丧失为特征的神经退行性疾病。我们最近的研究表明，硫氧还蛋白-1（Trx-1）在AD模型中可通过抑制NLRP1介导的神经元焦亡来保护神经元。然而，Trx-1是否能抑制NLRP3激活在很大程度上尚不清楚。在此，我们发现腺相关病毒介导的Trx-1过表达显著抑制了APP/PS1小鼠海马中NLRP3介导的焦亡。通过慢病毒转染成功获得了过表达Trx-1的小鼠海马神经元HT22细胞系。进一步研究表明，Trx-1过表达保护HT22细胞免受Aβ的神经细胞毒性作用。与体内实验结果一致，Trx-1过表达显著抑制了NLRP3的激活。相反，通过小干扰RNA转染敲低Trx-1进一步加剧了NLRP3的激活。机制上，Trx-1过表达在体内和体外均显著抑制了硫氧还蛋白相互作用蛋白（TXNIP）的增加，并削弱了TXNIP与NLRP3之间的相互作用。综上所述，在AD模型中，Trx-1通过调节TXNIP表达及其与NLRP3的相互作用来抑制NLRP3介导的焦亡。
