ABSTRACT
Deregulation of PTEN/Akt signalling has been recently implicated in the pathogenesis of Alzheimer's disease (AD), but the effects on the molecular processes underlying AD pathology have not yet been fully described. Here we report that overexpression of PTEN reduces tau phosphorylation in CHO cells. This effect was abrogated by mutant PTEN constructs with either a catalytically inactive point mutation (C124S) or with only inactive lipid phosphatase activity (G129E), suggesting an indirect, lipid phosphatase-dependent process. The predominant effects of PTEN on tau appeared to be mediated by reducing ERK1/2 activity, but were independent of Akt, GSK-3, JNK and the tau phosphatases PP1 and PP2A. 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 deregulation of PTEN may contribute towards the progression of tauopathy.
Subject(s)
Alzheimer Disease/enzymology , Cerebral Cortex/enzymology , PTEN Phosphohydrolase/metabolism , Phosphoinositide-3 Kinase Inhibitors , tau Proteins/metabolism , Animals , CHO Cells , Cerebral Cortex/cytology , Cricetinae , Cricetulus/genetics , Glycogen Synthase Kinase 3/metabolism , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Neurons/enzymology , PTEN Phosphohydrolase/analysis , PTEN Phosphohydrolase/genetics , Phosphatidate Phosphatase/genetics , Phosphatidate Phosphatase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Point Mutation , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , tau Proteins/analysisABSTRACT
Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a dual (protein tyrosine and lipid) phosphatase one of the functions of which is to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate to phosphatidylinositol-3,4-biphosphate thereby inhibiting phosphoinositide-dependent kinase activation of the cell survival kinase Akt. Akt activity is up regulated in Alzheimer's disease (AD) brain in parallel to the progression of neurofibrillary pathology. The present study determined whether altered expression of PTEN occurs in Alzheimer's disease brain. Western immunoblotting revealed no significant changes of PTEN protein levels in nuclear and membrane fractions of medial temporal cortex from a series of Alzheimer's disease and control cases. Similarly, no changes in PTEN protein levels, as determined by dot-blotting, were seen in temporal cortex homogenates from a separate series of Alzheimer's disease and control brains. A small but significant decrease in the levels of Ser(380) p-PTEN was seen in homogenates of Alzheimer's disease temporal cortex. Immunohistochemistry revealed PTEN immunoreactivity in a number of brain structures including neurons, capillaries and structures resembling oligodendrocytes and astrocytes. The majority of temporal cortex pyramidal neurons (93-100%) were PTEN immunopositive. The Alzheimer's disease cases had significantly lower numbers of total ( approximately 12% loss, P<0.02) and PTEN immunopositive ( approximately 15% loss, P<0.01) pyramidal neurons as compared to the control cases.
Subject(s)
Alzheimer Disease/metabolism , PTEN Phosphohydrolase/metabolism , Temporal Lobe/metabolism , Aged , Aged, 80 and over , Blotting, Western , Case-Control Studies , Female , Humans , Immunohistochemistry , MaleABSTRACT
Enzyme activities of the serine/threonine kinase Akt were compared in mid-temporal and mid-frontal cortices from Alzheimer's disease cases and matched controls. Activities (GSK-3alpha/beta fusion protein phosphorylation by immunoprecipitated Akt) were significantly increased in temporal cortex soluble fractions from Alzheimer's disease compared with non-disease controls and positive disease controls with another neurodegenerative disease. Temporal cortex soluble fraction Akt activities positively correlated with Braak staging for neurofibrillary changes. Frontal cortex soluble fraction activities were significantly reduced in positive disease compared with Alzheimer's disease cases and non-disease controls. Strong Ser Akt immunoreactivity was seen in Alzheimer's disease pyramidal neurons likely undergoing degeneration and in reactive astroglia. Non-disease and positive disease controls showed moderate Ser Akt immunostaining of occasional pyramidal neurons.
