Overexpression of inhibitor-1 or -2 of protein phosphatase-2A causes abnormal hyperphosphorylation of tau and cognitive impairment in the rat

Abstract

The activity of phosphoseryl/phosphothreonyl protein phosphatase (PP) -2A, the major human brain PP, is selectively decreased and is believed to be a cause of the abnormal hyperphosphorylation of tau in AD brain (Gong et al., J Neurochem 61:921-7, 1993; ibid J Neurochem 65:732-8, 1995). The activity of PP-2A is regulated by two inhibitor proteins, I1PP2A which is also known as PHAPI, mapmodulin, pp32, and LANP, and I2PP2A which is also known as PHAPII, Setα, and TAF-1β. Both the levels of mRNA and protein expression of I1PP2A and I2PP2A are elevated in the affected areas of AD brain, and are probably a cause of the decreased PP-2A activity and consequently the abnormal hyperphosphorylation of tau. Objective: To assess whether overexpression of I1PP2A- or I2PP2A-induced inhibition of PP-2A activity produces abnormal hyperphosphorylation of tau and behavioral impairment in the rat. We employed the adeno associated viral vector to induce expression of human brain I1PP2A or I2PP2A as GFP fusion proteins in rat brain. At various time periods from ∼ 9 weeks to ∼9 months after ICV injection with the virus, the effect of the overexpression of I1PP2A or I2PP2A on abnormal hyperphosphorylation, neurodegeneration, and cognition was studied. The infection of the newborn rat pups with AAV produced a long-lasting expression up to ∼9 months investigated. The expression of amino terminal half of I1PP2A which contains the inhibitory domain (Chen et al., J Biol Chem 283:10513-21, 2008) caused the abnormal hyperphosphorylation of tau at Thr231/Ser235, Ser262/356, and at Ser393/404 in the neocortex and a learning and memory impairment in Morris water maze. Expression of the carboxy terminal half of I2PP2A caused abnormal hyperphosphorylation of tau at Ser199, Ser262, and Ser396, a decrease in MAP 2, synaptophysin and synapsin 1, and impairment in learning in Morris water maze. This study suggests that overexpression of I1PP2A and/or I2PP2A previously observed in AD brain, causes abnormal hyperphosphorylation of tau and cognitive impairment. Thus, restoration of PP-2A activity by inhibiting the activity of I1PP2A and/or I2PP2A is a promising therapeutic approach for AD and related tauopathies.