Yang Hong-Qi, Sun Zhi-Kun, Zhao Yan-Xin, Pan Jing, Ba Mao-Wen, Lu Guo-Qiang, Ding Jian-Qing, Chen Hong-Zhuan, Chen Sheng-Di
Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
Neurochem Res. 2009 Mar;34(3):528-35. doi: 10.1007/s11064-008-9816-4. Epub 2008 Aug 29.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive impairment of memory and cognition. Previous data have shown that beta-amyloid (Abeta) cascade plays a central role in AD pathophysiology and thus drugs regulate amyloid precursor protein (APP) metabolism may have therapeutic potential. Here the effects of PMS777, a new cholinesterase inhibitor with anti-platelet activated factor activity, on APP processing were investigated. Using SH-SY5Y(APP695) cells, it showed that PMS777 treatment caused significant decreased secretion of sAPPalpha into the conditioned media without affecting cellular holoAPP synthesis. When PC12 cells were incubated with PMS777, the same effect was observed. The data also indicated that 10 muM PMS777 incubation decreased the release of Abeta42 into the cell media as compared with vehicle group in SH-SY5Y(APP695) cells. Pretreatment of cells with M-receptor scopolamine antagonized the decreased secretion of sAPPalpha induced by PMS777, but N-receptor alpha-bungarotoxin pretreatment did not have such an effect. These results indicated that PMS777 could modulate APP processing in vitro and that decreasing Abeta generation might demonstrate its therapeutic potential in AD.
阿尔茨海默病（AD）是一种神经退行性疾病，临床上以记忆力和认知能力的进行性损害为特征。先前的数据表明，β-淀粉样蛋白（Aβ）级联反应在AD的病理生理过程中起核心作用，因此调节淀粉样前体蛋白（APP）代谢的药物可能具有治疗潜力。在此，研究了一种具有抗血小板活化因子活性的新型胆碱酯酶抑制剂PMS777对APP加工的影响。使用SH-SY5Y（APP695）细胞，结果显示PMS777处理导致条件培养基中sAPPα的分泌显著减少，而不影响细胞内全长APP的合成。当PC12细胞与PMS777孵育时，也观察到了相同的效果。数据还表明，在SH-SY5Y（APP695）细胞中，与溶剂对照组相比，10μM PMS777孵育可减少Aβ42释放到细胞培养基中。用M受体东莨菪碱预处理细胞可拮抗PMS777诱导的sAPPα分泌减少，但N受体α-银环蛇毒素预处理则没有这种作用。这些结果表明，PMS777可在体外调节APP加工，减少Aβ生成可能显示其在AD中的治疗潜力。
