Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A

The down-regulation of protein phosphatase 2A (PP2A) activity is thought to play an important role in the formation of tau hyperphosphorylation in the Alzheimer's disease (AD) brain. Methylation of the PP2A catalytic subunit at the 1,309 site can potently activate PP2A for some substrates via the increasing recruitment of its regulatory subunits into the holoenzyme. A(3 is overproduced yet estrogen is deficient in the brains of the menopausal AD patients. Both A(3 and estrogen deficiency can interact with tau kinases such as protein kinase B and glycogen synthase kinase 3. In the current study, levels of demethylated (-m) PP2A (1,309) were significantly increased, and methylated (+m) PP2A (L309) were significantly decreased, which corresponded with the increased tau phosphorylation at the Tau-1 and PHF-1 sites in both mouse N2a cells carrying the human APP with Swedish mutation (APPswe) and transgenic APPswe/presenilin (PS) 1 (A246E) mice. These findings were replicated in wild-type N2a cells treated with A beta 25-35, and to a relatively larger extent, in both wild-type N2a cells and APPswe treated by okadaic acid, as well as in the brains of estrogen receptor (ER) alpha-/- and ER beta-/- mice that mimic the status of estrogen deficiency in menopausal AD patients. Together, these findings suggested that the increased demethylation of PP2A (1,309) mediated by A beta overproduction or estrogen deficiency (ER alpha-/- and ER beta-/-) may contribute to the reduced PP2A activity observed in the AD brain, resulting in the compromised dephosphorylation of abnormally hyperphosphorylated tau. (C) 2008 Elsevier Inc. All rights reserved.