Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice

Increase of inhibitor-2 of protein phosphatase-2A (I-2(PP2A)) is associated with protein phosphatase-2A (PP2A) inhibition and tau hyperphosphorylation in Alzheimer's disease (AD). Down-regulating I-2(PP2A) attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg2576). Here, we found that silencing I-2(PP2A) by hippocampal infusion of Lenti - siI(2)(PP2A) down-regulated I-2(PP2A) (similar to 45%) with reduction of tau phosphorylation/accumulation, improvement of memory deficits, and dendrite plasticity in 12-month-old human tau transgenic mice. Silencing I-2(PP2A) not only restored PP2A activity but also inhibited glycogen synthase kinase-3 beta (GSK-3 beta) with a significant activation of protein kinase A (PKA) and Akt. In HEK293/tau and N2a/tau cells, silencing I-2(PP2A) by pSUPER - siI(2)(PP2A) also significantly reduced tau hyperphosphorylation with restoration of PP2A activity and inhibition of GSK-3 beta, demonstrated by the decreased GSK-3 beta total protein and mRNA levels, and the increased inhibitory phosphorylation of GSK-3 beta at serine-9. Furthermore, activation of PKA but not Akt mediated the inhibition of GSK-3 beta by I-2(PP2A) silencing. We conclude that targeting I-2(PP2A) can improve tau pathologies and memory deficits in human tau transgenic mice, and activation of PKA contributes to GSK-3 beta inhibition induced by silencing I-2(PP2A) in vitro, suggesting that I-2(PP2A) is a promising multiple target of AD.