van Assema Danielle M E, van Berckel Bart N M
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Curr Pharm Des. 2016;22(38):5808-5816. doi: 10.2174/1381612822666160804094544.
Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia. One of the pathological hallmarks of the disease is amyloid deposition in the brain. The major cause of amyloid deposition in sporadic Alzheimer's disease is thought to be decreased brain clearance of amyloid. There is compelling preclinical evidence that the blood-brain barrier, a structure that maintains homeostasis in the central nervous system and protects the brain from harmful substances, plays an important role in amyloid clearance. Indeed, several dedicated transporter systems are present at the blood-brain barrier which may have a role in brain amyloid clearance, such as P-glycoprotein (P-gp). In vitro experiments and animal studies indicated increased amyloid deposition when P-gp was eliminated by pharmacological blockade or by genetic modification. And as decreased P-gp expression has been found in AD brains, P-gp became more and more a suspect. Using an imaging technique called positron emission tomography, P-gp transporter function was found to be decreased in Alzheimer's disease patients compared to healthy controls, further establishing the important role of P-gp in the pathogenesis of the disease. In this review, we summarize what is now known about P-gp in Alzheimer's disease pathology, as these transporters may provide a novel target for therapeutic strategies.
阿尔茨海默病是一种神经退行性疾病,也是最常见的痴呆形式。该疾病的病理特征之一是大脑中淀粉样蛋白沉积。散发性阿尔茨海默病中淀粉样蛋白沉积的主要原因被认为是大脑对淀粉样蛋白的清除减少。有令人信服的临床前证据表明,血脑屏障在淀粉样蛋白清除中起重要作用。血脑屏障是一种维持中枢神经系统内环境稳定并保护大脑免受有害物质侵害的结构。事实上,血脑屏障存在几种专门的转运系统,它们可能在大脑淀粉样蛋白清除中发挥作用,比如P-糖蛋白(P-gp)。体外实验和动物研究表明,通过药物阻断或基因改造消除P-gp后,淀粉样蛋白沉积增加。而且,在阿尔茨海默病患者大脑中发现P-gp表达降低,P-gp越来越受到怀疑。使用一种叫做正电子发射断层扫描的成像技术发现,与健康对照相比,阿尔茨海默病患者的P-gp转运功能降低,这进一步证实了P-gp在该疾病发病机制中的重要作用。在这篇综述中,我们总结了目前已知的P-gp在阿尔茨海默病病理学中的情况,因为这些转运蛋白可能为治疗策略提供一个新靶点。