脑内铁代谢紊乱在慢性脑低灌注致认知障碍发生中的作用

The onset and intervention mechanism of cognitive dysfunction is currently difficult to tackle the problem. Chronic cerebral hypoperfusion (CCH) is a major cause of cognitive dysfunction. Our research has found that CCH can lead to cognitive dysfunction, as well as abnormal iron metabolism in brain. However, the underlying damaging mechanisms of cognitive impairment induced by CCH have not been completely explored. In the present study, we determined the abnormal iron deposition and related iron metabolism protein in different cerebral regions of CCH rats. The relationship between iron accumulation in the brain and cognitive impairment was discussed. We will use gene transfer technology to upregulate the expression of relevant iron metabolism protein, and Si-RNA technology to silence the expression of relevant iron metabolism protein. This study aimed to observe the function of those protein and find out the therapeutic target during the CCH. Simultaneously, the changes of iron metabolism and cognitive function after deferoxamine treatment are observed. This study may provide new insight for treatment of cognitive dysfunction.

认知障碍的治疗是目前亟待解决的难题。慢性脑低灌注是导致认知障碍的主要原因之一。但慢性脑低灌注后认知障碍发生的确切机制尚不明确。我们前期研究发现慢性脑低灌注后脑内存在铁代谢紊乱并与认知障碍的发生密切相关。但铁代谢紊乱的发生、发展及如何导致认知障碍均未明确。在前期研究基础上，本课题拟建立慢性脑低灌注致认知障碍大鼠模型，采用基因转染技术上调铁代谢紊乱相关蛋白的表达和基因沉默技术阻断铁代谢紊乱相关蛋白的表达，考查相关蛋白的功能，寻找认知障碍发生过程中可干预的靶点；同时观察铁螯合剂去铁敏干预治疗后慢性脑低灌注过程中认知功能、铁代谢紊乱的变化，以获得慢性脑低灌注大鼠脑内铁代谢紊乱的变化、分布规律，及其与认知障碍发生之间的关系，力图阐明慢性脑低灌注导致认知障碍可能的发病机制，为认知障碍的治疗提供新的思路。

本项目通过对慢性脑低灌注致认知障碍大鼠模型的研究，发现慢性脑低灌注后大鼠出现认知障碍并发现脑内出现铁沉积，铁螯合剂治疗后可以改善大鼠认知障碍的程度，提示脑低灌注后可以导致铁代谢紊乱并与认知障碍的发生存在重要的联系。慢性脑低灌注后Ferritin-H、TfR、IRP1在神经元铁代谢紊乱中起着重要的调节变化，其中Ferritin-H可能在慢性低灌注后铁代谢紊乱过程中起重要的神经保护作用。慢性脑低灌注过程中白质损伤与铁代谢异常有明显相关性。体外培养的少突胶质细胞发育过程中TfR及FH起着重要的调节作用。同时我们改良并建立了单侧颈总动脉结扎的高血压大鼠低灌注模型，更符合临床实际发病的慢性脑低灌注动物模型。本项目研究对血管性认知障碍发病机制及干预进行了有益的探讨，并提出干预低灌注后铁代谢紊乱是可能使治疗认知障碍的一个重要方面。