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

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 (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-siI 2 PP2A ) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI 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-demethylation and elevation of PP2A C. Silencing I 2 PP2A 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 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 Aβ toxicities and improve the memory deficits in tg2576 mice, suggesting that I 2 PP2A could be a promising target for potential AD therapies.