Thioredoxin-1 inhibits NLRP3-mediated pyroptosis by regulating TXNIP in models of Alzheimer's disease.

在阿尔茨海默病模型中,硫氧还蛋白-1通过调节TXNIP抑制NLRP3介导的细胞焦亡

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作者:Jia Jinjing, Sheng Zixuan, Zhang Yuqian, Guo Lunxi, Chen Zhuo'er, Zhu Dongsheng, Zeng Xiansi, Liu Hongjun
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(25-35). 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.

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