Silencing PP2A Inhibitor by Lenti-shRNA Interference Ameliorates Neuropathologies and Memory Deficits in tg2576 Mice

2013 
Deficits of protein phosphatase-2A (PP2A) play a crucial role in tau hyperphosphorylation, amyloid 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 (I2PP2A). Therefore, in vivo silencing I2PP2A may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I2PP2A (LV-siI2PP2A) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI2PP2A decreased remarkably the elevated I2PP2A in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I2PP2A to PP2A catalytic subunit (PP2AC), repression of the inhibitory Leu309-demethylation and elevation of PP2AC. Silencing I2PP2A induced a long-lasting attenuation of amyloidogenesis in tg2576 mice with inhibition of amyloid precursor protein hyperphosphorylation and β-secretase activity, whereas simultaneous inhibition of PP2A abolished the antiamyloidogenic effects of I2PP2A silencing. Finally, silencing I2PP2A could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I2PP2A can efficiently rescue Aβ toxicities and improve the memory deficits in tg2576 mice, suggesting that I2PP2A could be a promising target for potential AD therapies.
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