转录因子 STAT3(信号转导和转录激活因子 3)的异常激活最近与阿尔茨海默病 (AD) 相关。STAT3 磷酸化对于与神经炎症相关的细胞因子分泌至关重要。此外,STAT3 可能充当 BACE1(β-APP 裂解酶-1)的转录调节因子,BACE1 是淀粉样蛋白 β (Aβ) 产生的关键酶。我们之前已经表明,野生型小鼠中 LPS 诱导的全身炎症引发的神经炎症和脑 BACE1 水平升高与 STAT3 激活增强有关。使用该 LPS 模型,本研究的目标是调查 STAT3 抑制剂给药是否可以预防神经炎症和异常 BACE1 调节。我们的结果表明,腹腔注射 Stattic,一种选择性抑制 STAT3 激活的分子,可降低海马中 LPS 诱导的小胶质细胞激活。此外,STAT3 抑制降低了由 LPS 全身给药触发的细胞因子 IL-6、IL-1β 和 TNF-α 的脑水平。与单独暴露于 LPS 的小鼠相比,在 LPS 和 Stattic 处理的小鼠海马体中观察到 BACE1 水平显着降低。总之,我们的结果表明 Stattic 可以保护海马体免受 AD 的两个病理特征的影响,并为进一步探索 STAT3 抑制在 AD 中的治疗潜力铺平了道路。与单独暴露于 LPS 的小鼠相比,在 LPS 和 Stattic 处理的小鼠海马体中观察到 BACE1 水平显着降低。总之,我们的结果表明 Stattic 可以保护海马体免受 AD 的两个病理特征的影响,并为进一步探索 STAT3 抑制在 AD 中的治疗潜力铺平了道路。与单独暴露于 LPS 的小鼠相比,在 LPS 和 Stattic 处理的小鼠海马体中观察到 BACE1 水平显着降低。总之,我们的结果表明 Stattic 可以保护海马体免受 AD 的两个病理特征的影响,并为进一步探索 STAT3 抑制在 AD 中的治疗潜力铺平了道路。
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STAT3 inhibition protects against neuroinflammation and BACE1 upregulation induced by systemic inflammation
Abnormal activation of the transcriptional factor STAT3 (signal transducer and activator of transcription 3) was recently associated with Alzheimer Disease (AD). STAT3 phosphorylation is critical for cytokine secretion linked to neuroinflammation. Moreover, STAT3 may act as a transcriptional regulator of BACE1 (β-APP cleaving enzyme-1), the key enzyme in amyloid β (Aβ) production. We have previously shown that neuroinflammation and increased brain BACE1 levels triggered by LPS-induced systemic inflammation in wild-type mice are associated with an enhanced STAT3 activation. Using this LPS model, the goal of this study was to investigate if a STAT3 inhibitor administration could be protective against neuroinflammation and abnormal BACE1 regulation. Our results show that intraperitoneal injection of Stattic, a molecule that selectively inhibits the activation of STAT3, decreases LPS-induced microglial activation in the hippocampus. In addition, STAT3 inhibition reduced brain levels of cytokines IL-6, IL-1β and TNF-α triggered by LPS systemic administration. A significant reduction of BACE1 levels was observed in the hippocampus of mice treated with LPS and Stattic compared to those exposed to LPS alone. Taking together, our results show that Stattic can protect hippocampus against two pathological hallmarks of AD, and pave the way for further explorations of the therapeutic potential of STAT3 inhibition in AD.