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, 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.