2-(α-羟基戊基)苯甲酸钾盐-dl-PHPB是抗脑缺血新药丁基苯酞(NBP)的前药，已完成Ⅰ期临床研究，并申请Ⅱ、Ⅲ期临床。最近的研究发现其在多种动物和细胞模型中具有明显的抗痴呆和调节相关信号通路作用。如血管性痴呆大鼠和SAMP8小鼠，PHPB都可明显提高认知能力。在APP695 SK-N-SH细胞及APP/PS1转基因小鼠中，dl-PHPB可减少Aβ和tau蛋白磷酸化。课题拟解决的关键问题是：阐明dl-PHPB抗AD的作用机制，寻找该药的靶点及用于AD治疗的可行性。研究内容包括，在APP/PS1小鼠及APP转基因细胞上，研究dl-PHPB对Aβ生成，降解及tau蛋白磷酸化相关信号通路的影响以及对胆碱能系统和NMDA受体相关的LTP的影响，并应用蛋白组学的方法，发现AD转基因小鼠脑中与AD发生发展相关的蛋白及信号系统的改变，dl-PHPB对它们的逆转作用，以期发展新的AD药物靶点。

Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB, with PCT global patents) is a candidate of prodrug of dl-NBP (anti-ischemic stroke). The phase I clinic trial of dl-PHPB was complete and the phase II clinic trial will be started soon. Recently it was found that dl-PHPB could improve cognition in several animal models, such as SAMP8 mice and vascular dementia rats. In APP 695 transgenic SK-N-SH cells and APP/PS1 transgenic mice PHPB were demonstrated to reduce ?-amyloid1-42 level and tau phosphorylation. The parent drug NBP was also demonstrated to inhibit ?-amyloid and tau phosphorylation. Dl-PHPB might be used for treatment of Alzheimer's disease (AD) as a new indication in future. Therefore, studying the mechanisms and the targets of PHPB for AD is important. In the present project we want to investigate the anti-dementia effect of PHPB on APP/PS1 mice (12 month) and study on the signal pathway for ?-amyloid generation and accumulation as well as the activity of the kinases for tau phosphorylation in the animal brain tissues and in APP transgenic cell lines. The NMDA dependent and acetylcholine related LTP will be also investigated in APP/PS1 mice after PHPB treatment. The proteomic study of APP/PS1 mice brain is planted to study to find differentially expressed proteins before and after PHPB treatment in transgenic animals and in control animals. It may help to find the new biomarkers of AD and to discover the targets of PHPB for treatment of AD. We possess the all techniques and equipment for above studies in our lab.