RbAp48在糖皮质激素介导的老年POCD中的机制研究

Post-operative cognitive dysfunction (POCD) mainly occurs in elderly patients, exhibits the impaired learning and memory as the major performance. The secretion extent, duration and rhythm of Glucocorticoids (GCs) can be changed by age and surgical stress. GCs can affect the hippocampus, which is rich in GCs receptors. The amount of histone-binding protein RbAp48 declines with age in dentate gyrus (DG), and the reduction of RbAp48 protein can lead to a decrease of histone acetylation and age-related memory loss through the CREB pathway. Our clinical study indicated that serum GCs level is directly related to POCD morbidity in the elderly. Preliminary experiments indicated that high-level of GCs and prolonged anesthesia can make a significant reduction of RbAp48 protein in DG with an impairment of spatial memory. Further study identified the inhibition of CREB plays an important role in the formation of this phenotype. We therefore hypothesized that the abnormal GCs in elderly patients during perioperative period changes the histone acetylation modified by RbAp48 in hippocampal neurons and induces POCD by inhibiting the critical pathway of learning and memory. Our work will firstly confirm the effect of surgical stress on the GCs secretion in aged mice, then discuss the role of abnormal GCs in cognitive function. Finally, we will reveal the correlative mechanism of histone acetylation modified by RbAp48 between GCs and cognitive function, and provide new methods for prevention and treatment of POCD.

术后认知功能障碍（POCD）主要发生于老年患者，以学习记忆受损为主要表现。年龄及手术应激可改变糖皮质激素(GCs)表达，影响富含GCs受体的海马功能。在海马齿状回中，组蛋白结合蛋白RbAp48与年龄呈负性关联，抑制RbAp48可降低组蛋白乙酰化水平，并通过CREB通路介导与衰老相关的记忆损伤。我们前期研究发现，老年患者术后血清GCs水平与老年POCD发病有直接关联；而高水平GCs刺激或胫骨骨折手术均可使老龄小鼠认知下降，且伴有齿状回RbAp48表达持续降低，CREB抑制在上述表型形成中起重要作用。我们假设，老年患者围术期GCs应激异常放大，改变海马RbAp48介导的组蛋白乙酰化水平，并通过抑制学习记忆的关键通路诱发老年POCD。本研究拟首先探明手术应激对老龄鼠GCs表达及学习记忆的影响，进而阐述RbAp48介导的组蛋白乙酰化在GCs与术后认知功能间的机制关联，为临床防治POCD提供新思路。

术后认知功能障碍(POCD)主要发生于老年患者，以学习记忆受损为主要表现。老龄是目前POCD研究中唯一明确的独立风险因素。年龄及手术应激可改变糖皮质激素(GCs)分泌，影响富含GCs受体(GR)的海马功能。在海马齿状回中，组蛋白结合蛋白RbAp48与年龄呈负性关联。GR的激活可上调核小体重构和组蛋白脱乙酰基酶(NuRD)复合体核心亚基组蛋白去乙酰化酶(HDAC2)蛋白表达，并对后者进行招募，影响BDNF等认知相关多种基因的组蛋白乙酰化水平。本研究使用长时程异氟醚麻醉建立小鼠POCD模型，并使用小鼠重复社交失败模型成功模拟老年围术期应激水平异常放大状态。在此基础上以HDAC2-RbAp48为核心，探讨GCs持续高水平对组蛋白乙酰化调控及其在术后认知功能障碍中的作用。研究结果显示：1)老年小鼠长时程异氟醚麻醉后存在 GCs水平持续升高。2)GCs持续高水平可加重小鼠长时程异氟醚麻醉后认知功能损伤。3)RbAp48-HDAC2共同调控的组蛋白去乙酰化过程是GCs持续高水平介导小鼠长时程异氟醚麻醉后认知功能损伤的重要机制。以上结果提示老年相关应激反应异常及围术期应激可能参与POCD的形成，本研究为临床预防POCD提供了潜在的方向，为临床围术期心理干预的开展提供了理论依据。