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

Abstract

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 (I2(PP2A)). Therefore, in vivo silencing I2(PP2A) may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I2(PP2A) (LV-siI2(PP2A)) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI2(PP2A) decreased remarkably the elevated I2(PP2A) in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I2(PP2A) to PP2A catalytic subunit (PP2AC), repression of the inhibitory Leu309-demethylation and elevation of PP2AC. Silencing I2(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 I2(PP2A) silencing. Finally, silencing I2(PP2A) could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I2(PP2A) can efficiently rescue Aβ toxicities and improve the memory deficits in tg2576 mice, suggesting that I2(PP2A) could be a promising target for potential AD therapies.

Cyclin‐Dependent kinase 5 targeting prevents β‐Amyloid aggregation involving glycogen synthase kinase 3β and phosphatases

“…Furthermore, GSK3b phosphorylated at Ser9 induces PP2A activity, thereby preventing amyloidosis (Noh et al, 2013). However, our data suggest that, when shCDK5miR loses its efficiency for reducing CDK5 activity at 1 year postinjection (Castro-Alvarez et al, 2014a), there is a concomitant loss of PP2A activity as well as a loss of efficiency on the reversion of APP processing and the presence of extracellular plaques, suggesting a close relationship between CDK5 and PP2A in the control of bA aggregation, possibly through the regulation of GSK3b, which could be supported by previous studies indicating that PP2A and GSK3b are involved in bA accumulation (Ryder et al, 2003;Wen et al, 2008a;Liu et al, 2013).…”

“…The most important phosphatases associated with AD are PP1 and PP2A, which are reported to have the highest tau dephosphorylation activity (Liu et al, 2005). These phosphatases, in turn, have control over other substrates involved in the signaling pathway of AD (Ducruet et al, 2005;Braithwaite et al, 2012;Liu et al, 2013). PP1 can activate GSK3 via dephosphorylation at Ser9 (Bennecib et al, 2000;Hernandez et al, 2010), and PP2A can dephosphorylate and regulate AKT, thereby inhibiting its action on GSK3 (Mora et al, 2002;Resjo et al, 2002).…”

Erythropoietin attenuates Alzheimer-like memory impairments and pathological changes induced by amyloid β42 in mice

“…diameter) in an environment rich with extra maze cues on the 7th day after injection as described previously (Liu et al, 2013). Each experiment included 4 trials/day for 6 consecutive days with a 15-min intertrial interval.…”

Epigenetic regulation of estrogen-dependent memory

“…These findings suggest an essential role for PP1 in regulating histone modifications associated with enhanced synaptic plasticity and mnemonic processes. Although other protein phosphatases, such as PP2A, have been implicated in hippocampal synaptic plasticity and function (Liu et al, 2013; Lorrio et al, 2013), their role in histone dephosphorylation is unknown.…”