Effects of PTEN inhibition on regulation of tau phosphorylation in an okadaic acid-induced neurodegeneration model.
One of pathological hallmarks of Alzheimer's disease (AD) is neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. The molecular mechanisms underlying the regulation of tau hyperphosphorylation remain largely unclear. The phosphoinositide 3-kinase (PI3K)/Akt pathway has been implicated in the pathogenesis of AD, however, 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, knockdown of PTEN reduces the tau hyperphosphorylation by OA in SH-SY5Y cells and increases cell proliferation and survival. The effect of PTEN suppression on tau dephosphorylation appeared to be mediated by inhibition of glycogen synthase kinase 3 while enhancing the Akt activity. Reduction of tau phosphorylation was also observed in the OA-induced parental SH-SY5Y cells co-treated with bisperoxovanadate (bpv), a potent PTEN inhibitor. Our studies provide evidence for an effect of PTEN on the phosphorylation of tau in AD pathogenesis and give some insight into the mechanisms through which suppression of PTEN expression may contribute towards the amelioration of tauopathy, implying that pharmacological intervention of PTEN may be a new therapeutic approach for the treatment of AD.
Department of Pharmacology, College of Pharmacy, 88 Jiao-Tong Road, Fujian Medical University, Fuzhou 350004, Fujian, PR China.
Zhou
Z
Chen
Bin
B
Chen
Wen-Fang
WF
Xu
Rong-Fang
RF
Liu
Jian
J
Yang
Chang-Xi
CX
Yu
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D019319:Okadaic Acid / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D016875:tau Proteins; D019319:Okadaic Acid; D038362:Glycogen Synthase Kinase 3; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase