Abstract：
Alzheimer\'s disease (AD) is one of the leading causes of death throughout the world. Z-DNA binding protein 1 (ZBP1), a DNA-related gene, is associated with inflammation, and its expression is altered in AD brain. We aimed to elucidate the exact role of ZBP1 in AD development and its potential regulatory mechanism. First, we constructed both in vivo and in vitro models of AD and investigated the ZBP1 expression profile. A loss-of-function assay was performed by transfecting lentivirus carrying ZBP1 short hairpin RNA (shRNA). By evaluating cell death, oxidative stress, inflammation response and pyroptosis, the function of ZBP1 was validated. Finally, the correlation between ZBP1 and interferon regulatory factor 3 (IRF3) was verified. We also performed rescue experiments to validate the crucial role of IRF3 in ZBP1-mediated AD progression. According to our results, ZBP1 was upregulated in AD rat tissue and AD neurons. Silencing ZBP1 dramatically decreased cell injury, oxidative stress and inflammation in AD neurons and improved the cognitive function of AD rats. Additionally, IRF3 expression and phosphorylation were significantly elevated during AD development and positively correlated with ZBP1. Taken together, silencing ZBP1 suppressed cell injury and pyroptosis of AD neurons and improved cognitive function of AD rats via inhibiting IRF3. These findings might provide a novel insight for AD target diagnosis and therapy.
摘要：
阿尔茨海默病(Alzheimer’sdisease,AD)是世界上主要的死亡原因之一。Z-DNA结合蛋白1(ZBP1),DNA相关基因,与炎症有关，它在AD大脑中的表达发生了改变。我们旨在阐明ZBP1在AD发展中的确切作用及其潜在的调控机制。首先,我们构建了AD的体内和体外模型，并研究了ZBP1表达谱。通过转染携带ZBP1短发夹RNA(shRNA)的慢病毒进行功能丧失测定。通过评估细胞死亡，氧化应激，炎症反应和焦亡，ZBP1的功能得到验证。最后,证实ZBP1与干扰素调节因子3(IRF3)的相关性。我们还进行了拯救实验以验证IRF3在ZBP1介导的AD进展中的关键作用。根据我们的结果,ZBP1在AD大鼠组织和AD神经元中上调。沉默ZBP1可显着减少细胞损伤，AD神经元的氧化应激和炎症反应,改善AD大鼠的认知功能。此外,IRF3的表达和磷酸化在AD发育过程中显著升高,与ZBP1呈正相关。一起来看,沉默ZBP1可通过抑制IRF3抑制AD大鼠的细胞损伤和神经元焦凋亡,改善AD大鼠的认知功能。这些发现可能为AD的靶向诊断和治疗提供新的见解。
