雷公藤氯内酯醇抑制NLRP3炎症小体活化减轻Alzheimer病神经炎症反应

There is still no effective treatment for Alzheimer's disease (AD). Neuroinflammation is key pathological change in the occurrence and development of AD. Furthermore, NLRP3 inflammasome is playing an important role in inflammation and tissue damage in AD. Our previous studies have found that Tripterygium extracts tripchlorolide T4, which has low toxicity and high pharmacological activity, can ameliorate cognitive deficits in 5XFAD APP/PS1 transgenic mice, glial cell activation and inflammatory mediators release. These results suggest that T4 may be a promising novel drug for AD, but its mechanism of anti-neuroinflammation in AD is still blurred. Depending on the previous investigations, we draw the hypothesis that T4 relieves neuroinflammation via affecting NLRP3 inflammasome activity. The NLRP3 activity is involved in NF-κB nuclear transfer, caspase 1, ASC activity, and cathepsin B activity, which is concerning about microglia up-taking and clearing Aβ. Additionally, the possible role of T4 in affecting NLRP3 inflammasome activity will be carried out in primary microglia culture, BV2 microglial cell line and 5XFAD APP/PS1 transgenic mice by western blot, real-time PCR, flow cytometry and lentivirus transfection. It will further confirm the effective treatment of T4 for AD in both theory and experiment.

阿尔茨海默病（AD）目前仍缺乏有效的治疗手段。神经炎症反应与AD病程的发生和发展密切相关，NLRP3炎症小体是AD神经炎症反应的重要环节。我们前期研究发现天然雷公藤减毒单体-雷公藤氯内酯醇（T4）可以提高AD转基因小鼠学习记忆功能，抑制胶质细胞活化和炎症介质生成，具有潜在防治AD作用，但其影响神经炎症的机制还有待于进一步探讨。为此我们提出假说：T4可能通过影响NF-κB核转位、抑制caspase-1和ASC活性、促进Aβ吞噬清除、抑制cathepsin B活性，最终影响NLRP3炎症小体活化，减轻神经炎症级联反应。为验证这一假说，我们以原代小胶质细胞、BV2细胞株和5XFAD APP/ PS1转基因小鼠为模型，采用western blot、real-time PCR、流式细胞术、慢病毒转染等手段，探讨T4影响NLRP3炎症小体的可能机制，为进一步应用T4防治AD提供客观的理论和实验依据。

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