beta淀粉样肽（Abeta）沉积是老年性痴呆(AD)的病理标志，APP Thr668位点磷酸化、beta-/gamma-分泌酶活性均可促进Abeta生成。因此，降低Thr668-pAPP水平和/或降低beta-/gamma-分泌酶活性对防治AD有潜在应用价值。申请者最近研究显示：针对PP2A抑制因子-2（I2PP2A）的 siRNA 慢病毒表达载体转染Tg2576转基因鼠，可降低Abeta水平。本项目拟在细胞水平进一步确定下调 I2PP2A 对APP磷酸化水平及分泌酶活性的影响及相关分子机制；采用慢病毒表达载体转染Tg2576和APPSwe×PS1M126V×TauP301L转基因鼠，研究下调 I2PP2A 表达水平对转基因鼠的AD-样病理和行为异常的改善作用。基于下调I2PP2A可同时逆转tau过度磷酸化和减少Abeta，该项目研究结果有望使I2PP2A成为AD有效药物研发的新靶点。

Abeta protein deposits is one of pathological markers of Alzheimer's disease (AD). Both the phosphorylated level of amyloid precursor protein (APP) at Thr668 and beta-/gamma-secretase activities promote Abeta production. So, decreasing the level of Thr668-pAPP and/or beta-/gamma- secretase activities have potent application values. The preliminary data have shown that downregulation of I2PP2A by intracranial infusion of lentivirus (Lenti-siI2PP2A) remarkably reduces abeta accumulation in Tg2576 mice. The project will investigate the effects of knockdown I2PP2A on phosphorylated Thr668-APP level and beta-/gamma- secretase activities and the underlying mechanisms in cell lines. We will also study ameliorative effects of knockdown I2PP2A on AD like pathophysiology and cognitive deficits of Tg2576 mice and a triple transgenic model of AD (3×Tg-AD) harboring three mutant genes: β-amyloid precursor protein (βAPPSwe), presenilin-1 (PS1M146V), and tauP301L, through intracranial infusion of lenti-siI2PP2A. Knockdown I2PP2A could attenuate tau phosphorylation and decrease Abeta level, so the results provide I2PP2A as a new target for drug research and development in AD.