P-糖蛋白在早老性痴呆症治疗中的作用及临床意义

The Function and Clinical Significance of P-glycoprotein in the Treatment of Alzheimer's Disease

早老性痴呆症(Alzheimer's disease,AD)是一种由脑内β-淀粉样蛋白积聚而引起的慢性中枢神经系统退行性疾病,多发于年长者,对老年人的身心健康造成严重危害。P-糖蛋白(P-glycoprotein,P-GP)属于ATP结合盒(ATP-binding cassette,ABC)超家族,是被认为与多药耐药(Multidrug resistance,MDR)相关的外排转运蛋白。但是P-GP不仅参与血脑屏障的药物外排,还参与AD状态下脑内β-淀粉样蛋白的外排,进而达到缓解早老性痴呆症病情的作用。然而AD状态下脑内β-淀粉样蛋白聚集又会下调脑内P-糖蛋白表达,从而使其外排作用减弱,进一步加重AD的病情发展。因此P-GP在早老性痴呆症的治疗中起着关键作用,了解其作用机制对于AD的治疗以及预防具有极其重要的临床意义。现阶段已有研究开始对相应机制的药物进行筛选和开发,说明P-GP治疗可能成为一个十分具有前景的AD治疗方向之一。但是,β-淀粉样蛋白对P-GP的影响机制和恢复P-GP表达的AD治疗法的疗效以及可能造成的副作用尚不明确,仍然需要进一步的研究加以阐明。

Alzheimer＇s disease（AD） is a chronic central nervous system degenerative disease caused by the accumulation of beta amyloid in the brain,which often occurs in the elderly and causes serious harm to the physical and mental health. The P-glycoprotein（P-GP）,belonging to the ATP-binding cassette（ABC） super-families,was first identified as an efflux transporter related to multidrug resistance（MDR）. P-GP is close associated with the drug exocytosis at the blood brain barrier,and is also involved in the efflux of beta amyloid in the brain of AD patients,leading to the alleviation of the AD development. On the other hand,the accumulation of beta amyloid protein may down-regulate the P-glycoprotein expression,which in turn attenuates the efflux of beta amyloid and aggravates the AD development. Therefore,P-glycoprotein plays a key role in the treatment of Alzheimer＇ s disease. To advance the treatment and prevention of AD,it is of great importance for us to understand that the role P-glycoprotein may be played in AD development,in terms of either mechanism or function illumination. At present,the deep understanding in the P-glycoprotein has driven the screen and development of novel drugs for AD treatment,which may be one of the research areas with promising prospective for AD treatment. However,the mechanism underlying the impact of beta amyloid protein on P-glycoprotein function,P-glycoprotein-based treatment and the related adverse effect is still not fully understood and thus is needs further investigation.