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

Abstract

Increase of inhibitor-2 of protein phosphatase-2A I2PP2A is associated with protein phosphatase-2A (PP2A) inhibition and tau hyperphosphorylation in Alzheimer's disease (AD). Down-regulating I2PP2A attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg2576). Here, we found that silencing I2PP2A by hippocampal infusion of Lenti - siI2PP2A down-regulated I2PP2A (~45%) with reduction of tau phosphorylation/accumulation, improvement of memory deficits, and dendritic plasticity in 12-month-old human tau transgenic mice. Silencing I2PP2A not only restored PP2A activity but also inhibited glycogen synthase kinase-3ß (GSK-3ß) with a significant activation of protein kinase A (PKA) and Akt. In HEK293/tau and N2a/tau cells, silencing I2PP2A by pSUPER - siI2PP2A also significantly reduced tau hyperphosphorylation with restoration of PP2A activity and inhibition of GSK-3ß, demonstrated by the decreased GSK-3ß total protein and mRNA levels, and the increased inhibitory phosphorylation of GSK-3ß at serine-9. Furthermore, activation of PKA but not Akt mediated the inhibition of GSK-3ß by I2PP2A silencing. We conclude that targeting I2PP2A can improve tau pathologies and memory deficits in human tau transgenic mice, and activation of PKA contributes to GSK-3ß inhibition induced by silencing I2PP2A in vitro, suggesting that I2PP2A is a promising multiple target of AD. © 2014 Zhang, Ma, Li, Zhang, Shi, Wei, Luo, Wang, Wang and Liu.