Silencing PP2A Inhibitor by Lenti-shRNA Interference Ameliorates Neuropathologies and Memory Deficits in tg2576 Mice
Silencing PP2A Inhibitor by Lenti-shRNA Interference Ameliorates Neuropathologies and Memory Deficits in tg2576 Mice
复制标题
通过 Lenti-shRNA 干扰沉默 PP2A 抑制剂可改善 tg2576 小鼠的神经病理学和记忆缺陷
DOI：
10.1038/mt.2013.189
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发表时间：
2013-12-01
影响因子：
12.4
通讯作者：
Wang, Jian-Zhi
中科院分区：
文献类型：
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作者：
Liu, Gong-Ping;Wei, Wei;Wang, Jian-Zhi
蛋白磷酸酶-2A（PP 2A）的缺陷在tau蛋白过度磷酸化、环状蛋白过度产生和阿尔茨海默病（AD）的突触抑制中起关键作用，其中PP 2A被内源性增加的抑制蛋白，即PP 2A的抑制剂-2（I-2（PP 2A））失活。因此，在体内沉默I-2（PP 2A）可以挽救PP 2A和减轻AD神经变性。通过向11月龄tg 2576小鼠海马和额叶皮层注射靶向I-2（PP 2A）的慢病毒-shRNA（LV-sil（2）（PP 2A）），我们证明LV-sil（2）（PP 2A）的表达在mRNA和蛋白水平上显著降低了I-2（PP 2A）的升高。同时，PP 2A活性恢复的机制涉及I-2（PP 2A）与PP 2A催化亚基（PP 2A（C））的抑制性结合的减少、抑制性Leu 309-去甲基化的抑制和PP 2A（C）的升高。沉默I-2（PP 2A）通过抑制淀粉样前体蛋白过度磷酸化和P-分泌酶活性诱导tg 2576小鼠中环状淀粉样蛋白生成的持久衰减，而同时抑制PP 2A则消除了I-2（PP 2A）沉默的抗淀粉样蛋白生成作用。沉默I-2（PP 2A）可改善tg 2576小鼠的学习记忆功能，并保留一些记忆相关成分。我们的数据显示，靶向I-2（PP 2A）可以有效地挽救A β毒性并改善tg 2576小鼠的记忆缺陷，这表明I-2（PP 2A）可能是潜在的AD治疗的有希望的靶点。
Deficits of protein phosphatase-2A (PP2A) play a crucial role in tau hyperphosphorylation, annyloid overproduction, and synaptic suppression of Alzheimer's disease (AD), in which PP2A is inactivated by the endogenously increased inhibitory protein, namely inhibitor-2 of PP2A (I-2(PP2A)). Therefore, in vivo silencing I-2(PP2A) may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I-2(PP2A) (LV-sil(2)(PP2A)) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-sil(2)(PP2A) decreased remarkably the elevated I-2(PP2A) in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I-2(PP2A) to PP2A catalytic subunit (PP2A(C)), repression of the inhibitory Leu309-dennethylation and elevation of PP2A(C). Silencing I-2(PP2A) induced a long-lasting attenuation of annyloidogenesis in tg2576 mice with inhibition of amyloid precursor protein hyperphosphorylation and P-secretase activity, whereas simultaneous inhibition of PP2A abolished the antiamyloidogenic effects of I-2(PP2A) silencing. Finally, silencing I-2(PP2A) could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I-2(PP2A) can efficiently rescue A beta toxicities and improve the memory deficits in tg2576 mice, suggesting that I-2(PP2A) could be a promising target for potential AD therapies.