炎症因子IL-1β介导的IFITM3调控γ分泌酶在术后认知功能障碍发生中的作用及机制研究

术后认知功能障碍（POCD）是老年患者手术麻醉后常见并发症，其机制尚不明确。POCD和阿尔兹海默病（AD）可能具有某些相似的分子机制。最新研究表明，在AD中，干扰素诱导跨膜蛋白3（IFITM3）可通过调控γ-分泌酶活性影响β淀粉样蛋白（Aβ）聚集，增加AD的风险，但IFITM3在POCD中是否发挥作用尚不明确。我们预实验发现，老年小鼠麻醉手术后引起认知功能障碍并伴随IFITM3的增高。此外，在POCD的发病机制中，同样存在AD中诱导IFITM3表达增高的因素——炎症因子IL-1β。因此，我们推测，麻醉手术后，脑内升高的IL-1β引起IFITM3表达升高，IFITM3的增多上调γ分泌酶的活性，增加Aβ40 及Aβ42表达，最终引发POCD。本课题拟建立老年小鼠POCD模型，通过分子生物学、行为学、基因敲除等方法探究上述假说。本研究将进一步完善POCD的病理机制，为POCD的治疗提供新思路。

Postoperative cognitive dysfunction (POCD) is a common complication after surgery and anesthesia in elderly patients, and its mechanism is not clear. POCD and Alzheimer's disease (AD) may have some similar molecular mechanisms. The latest research shows that in AD, interferon-induced transmembrane protein 3 (IFITM3) can affect β-amyloid (Aβ) aggregation by regulating γ-secretase activity and increase the risk of AD, but whether IFITM3 plays a role in POCD is still unclear. Our preliminary experiments have found that after anesthesia and surgery in elderly mice, mice developed cognitive dysfunction accompanied by an increase in IFITM3. In addition, in the pathogenesis of POCD, there also exist factors that induce the increased expression of IFITM3 in AD——inflammatory factor IL-1β. Therefore, we speculate that after anesthesia and surgery, elevated inflammatory factors in the brain cause the increase of of IFITM3, and the increase of IFITM3 up-regulates the activity of γ-secretase, increases the aggregation of Aβ40 and Aβ42, and finally triggers POCD. This project intends to establish a POCD model in aged mice, and explore the above hypotheses through molecular biology, behavior, gene knockout and other methods. This study will further improve the etiology and pathological mechanism of POCD, and ultimately provide new ideas for the treatment of POCD.