Thioredoxin-1 inhibits NLRP3-mediated pyroptosis by regulating TXNIP in models of Alzheimer’s disease
Jing Jia, Zixuan Sheng, Yuqian Zhang, Lunxi Guo, Z.-L. Chen, Dongsheng Zhu, Xiansi Zeng, Hongjun Liu
Abstract
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.