MMP9介导的NGF代谢异常致中枢胆碱能神经损伤——术后认知功能障碍的新机制

Postoperative cognitive dysfunction (POCD) , which can increases the morbidity and mortality, has been an important clinical issue to be solved. However, the mechanism of POCD is not clear yet. Our previous studies demonstrated that the injury of central cholinergic neuron played an important role in the happen of POCD of aged mice. While, why central cholinergic neuron are injured after surgery is still vague. We hypothesized that MMP9 secreted by blood neutrophils which were activated by surgery could increase the permeability of blood brain barrier (BBB) and then cross BBB into central neural system, which made more NGF degraded. As a result, cholinergic neuron was injured without enough NGF, and then POCD occurred. In the present study, with the appendectomy model of aged mice, many methods including over expression of NGF with lentivirus, MMP9 knock out mice, bone marrow transplantation will be adopted to verify our hypothesis. Our studies will present a new mechanism of POCD and provide new targets for the therapy of POCD in clinical setting.

术后认知功能障碍（POCD）可以增加围术期发病率和死亡率，已经成为一个临床上亟待解决的重要问题，但其发病机制仍然不清楚。我们先前的研究发现术后中枢胆碱能神经元损伤是老年小鼠POCD发生的重要原因，但是胆碱能神经损伤的原因不明。我们假设手术激活的外周中性粒细胞分泌MMP9，中性粒细胞源性MMP9不但增加血脑屏障的通透性，而且通过受损的血脑屏障进入中枢，加速了神经生长因子（NGF）的降解，从而使中枢胆碱能神经元因缺乏NGF营养而受到损伤，最终造成认知功能发生障碍。因此本研究拟采用老年小鼠的阑尾切除术模型，应用慢病毒过表达NGF或者敲除MMP9基因和骨髓移植等技术来证明上述假说。从而提出POCD的新机制，为临床上防治POCD提供新的靶点。

术后认知功能障碍（POCD）可以增加围术期发病率和死亡率，目前已知老龄是POCD最主要的危险因素，先前的研究发现中枢胆碱能系统损伤在老年动物POCD的发生中有着重要作用，但其确切机制尚不明确。神经生长因子（NGF）具有维持胆碱能神经正常形态结构和生化功能的作用，而成熟NGF的降解和失活则是通过基质金属蛋白酶-9（MMP-9）催化介导的。因此我们假设手术激活的外周中性粒细胞分泌MMP-9，中性粒细胞源性MMP-9不但增加血脑屏障（BBB）的通透性，而且通过受损的BBB进入中枢，使成熟NGF的降解增加，从而使中枢胆碱能神经元因缺乏NGF营养而受到损伤，最终造成认知功能障碍。结果显示，老年小鼠阑尾术后学习和记忆能力下降，中枢胆碱能系统受损，BBB完整性破坏，成熟NGF降解增加，而MMP-9基因敲除和中性粒细胞消除则可以减轻手术造成的学习和记忆能力下降和胆碱能神经系统损伤。本研究证明了手术后MMP-9表达上调造成NGF降解增加是POCD发病的重要原因，这提示我们可以将NGF/MMP-9作为新的干预靶点，对POCD进行预防和治疗，从而减轻病人的痛苦，提高术后生活质量。