One of pathological hallmarks of Alzheimers disease (AD) is neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau.The molecular mechanisms underlying the regulation of tau hyperphosphorylation remain largely unclear.While the phosphoinositide 3-kinase (PI3K)/Akt pathway has been implicated in the pathogenesis of AD, potential functions and role of tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in AD pathogenesis have not been fully explored.Here, we report that okadaic acid (OA)-induced tau phosphorylation is accompanied by PTEN induction, constitutive knockdown of PTEN reduces the tau hyporphosphorylation by OA in SH-SY5Y cells and increases cell proliferation and survival.The effect of PTEN downmgulation on tau dephosphorylation appeared to be mediated by inhibition of glycogen synthase kinase-3 while enhancing the Akt activity.Our studies provide evidence for an effect of PTEN on the phosphorylation of tau in AD pathogenesis, and provide some insight into the mechanisms through which down-regulation of PTEN may contribute towards the amelioration of tauopathy.