Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

Mol Neurobiol. 2016 Sep;53(7):4787-97. doi: 10.1007/s12035-015-9405-x. Epub 2015 Sep 2.

Abstract

Glycogen synthase kinase-3β (GSK-3β) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer's disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCε activated Akt and inactivated GSK-3β by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3β. Combination of PKCε activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3β than each independent treatment, to suppress amyloid β (Aβ)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.

Keywords: Akt; Alzheimer’s disease; GSK-3β; PKCε; Protein tyrosine phosphatase 1B; Tau.

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Mice, Transgenic
  • Organ Culture Techniques
  • PC12 Cells
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Protein Kinase C-epsilon / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Rats
  • Rats, Wistar
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • tau Proteins
  • Glycogen Synthase Kinase 3 beta
  • Protein Kinase C-epsilon
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse