Abstract：
Alzheimer\'s disease (AD) is the most common neurodegenerative disease all over the world. In the last decade, accumulating proofs have evidenced that neuroinflammation is intimately implicated in the pathogenesis of AD and activation of NOD-like receptor family pyrin domain-containing 1 (NLRP1) inflammasome can induce neuronal pyroptosis and in turn lead to neuronal loss in AD. Thioredoxin-1 (Trx-1), a multifunctional molecule with anti-inflammation in human tissues, displays crucial neuroprotective roles in AD. Our previous research preliminarily found that Trx-1 inhibition enhanced the expression of NLRP1, caspase-1, and gasdermin D (GSDMD) in Aβ25-35-treated PC12 cells. However, it is largely unknown if Trx-1 can inhibit NLRP1-mediated neuronal pyroptosis in AD neurons. In this study, it was verified that the protein levels of NLRP1, caspase-1, and GSDMD were significantly increased in Aβ25-35-treated mouse HT22 and primary hippocampal neurons. Suppression of Trx-1 with PX-12, a selective inhibitor of Trx-1, or Trx-1 knockdown further activated NLRP1-mediated neuronal pyroptosis. On the contrary, lentivirus infection-mediated Trx-1 overexpression in differentiated PC12 cells dramatically reversed expression of NLRP1, caspase-1, and GSDMD. Furthermore, Trx-1 overexpression mediated by adeno-associated virus in the hippocampal tissues of APP/PS1 mice likewise attenuated the activation of NLRP1-mediated neuronal pyroptosis, as well as reduced the hippocampal deposition of Aβ and ameliorated the cognitive function of APP/PS1 mice. In conclusion, this article predicates a novel molecular mechanism by which Trx-1 exploits neuroprotection through attenuating NLRP1-mediated neuronal pyroptosis in AD models, suggesting that Trx-1 may be a promising therapeutic target for AD.
摘要：
阿尔茨海默病(Alzheimer’sdisease,AD)是世界上最常见的神经退行性疾病。在过去的十年里，越来越多的证据表明，神经炎症与AD的发病机理密切相关，含NOD样受体家族pyrin结构域1（NLRP1）炎性体的激活可诱导神经元焦亡，进而导致AD的神经元丢失。硫氧还蛋白-1(Trx-1),在人体组织中具有抗炎作用的多功能分子，在AD中显示出至关重要的神经保护作用。我们先前的研究初步发现，抑制Trx-1可增强Aβ25-35处理的PC12细胞中NLRP1，caspase-1和gasderminD（GSDMD）的表达。然而,目前尚不清楚Trx-1能否抑制AD神经元中NLRP1介导的神经元焦亡。在这项研究中,已证实，在Aβ25-35处理的小鼠HT22和原代海马神经元中，NLRP1，caspase-1和GSDMD的蛋白水平显着增加。用选择性Trx-1抑制剂PX-12抑制Trx-1或Trx-1敲低进一步激活NLRP1介导的神经元焦亡。相反,在分化的PC12细胞中慢病毒感染介导的Trx-1过表达显著逆转了NLRP1、caspase-1和GSDMD的表达。此外，APP/PS1小鼠海马组织中腺相关病毒介导的Trx-1过表达同样减弱了NLRP1介导的神经元焦亡的激活，并减少Aβ的海马沉积，改善APP/PS1小鼠的认知功能。总之,本文预测了一种新的分子机制，Trx-1通过减弱AD模型中NLRP1介导的神经元焦亡来利用神经保护作用，提示Trx-1可能是一个有希望的AD治疗靶点。
