Phosphorylation events mediated by protein kinase Cα and ε participate in regulation of tau steady-state levels and generation of certain 'Alzheimer-like' phospho-epitopes

  • Boyce J
  • Shea T
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Hyperactivation of protein kinase C (PKC) in intact neuroblastoma cells by several methods increases site-specific tau phosphorylation as shown by increases in paired helical filament-1 (PHF-1) and ALZ-50 but not AT-8 immunoreactivity. In the present study, the influence of PKC on tau metabolism was further examined by isoform-specific antisense oligonucleotide-mediated PKC downregulation in human SH-SY-5Y neuroblastoma cells and by generation of stably-transfected subclones expressing isoform-specific anti-PKC mRNA sequences. Downregulation of PKCε by both of these methods reduced PHF-1 and ALZ-50 immunoreactivity, suggesting that this PKC isoform, perhaps via downstream kinase cascades, regulated tau phosphorylation events that normally generate these epitopes. By contrast, downregulation of either PKCε or PKCα reduced immunoreactivity towards the phosphate-independent anti-tau antibodies 5E2 and JM, suggesting that both of these isoforms participated in regulation of tau steady-state levels. Downregulation of PKCβ did not affect any of the above changes. The above roles were apparently unique for PKCε and PKCα, since activation of multiple PKC isoforms by phorbol ester treatment and/or other calcium-dependent kinase(s) by ionophore-mediated calcium influx could not compensate for downregulation of PKCε or PKCα in maintaining tau steady-state levels or PHF-1/ALZ-50 immunoreactivity, respectively. These findings suggest that hyperactivation of signal transduction pathways, including those regulated by PKC, could evoke changes in neuronal cells reminiscent of those seen in affected neurons in Alzheimer's disease.

Author-supplied keywords

  • Alzheimer's disease
  • Antisense oligonucleotides
  • Paired helical filaments
  • Phosphorylation
  • Protein kinase C
  • Signal transduction
  • tau

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  • John J. Boyce

  • Thomas B. Shea

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