Apolipoprotein E and beta-amyloid (1-42) regulation of glycogen synthase kinase-3beta

J Neurochem. 2003 Dec;87(5):1152-64. doi: 10.1046/j.1471-4159.2003.02088.x.

Abstract

Glycogen synthase kinase-3beta (GSK-3beta) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and beta-amyloid (Abeta) 1-42 on GSK-3beta and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca2+-independent and early activation of GSK-3beta. ApoE4 effects were biphasic, with an early strong GSK-3beta activation that was partially dependent on extracellular Ca2+, followed by a GSK-3beta inactivation. ApoE4 also activated PKC-alpha and PKB possibly giving the subsequent GSK-3beta inhibition. Abeta(1-42) effects were also biphasic with a strong activation dependent partially on extracellular Ca2+ followed by an inactivation. Abeta(1-42) induced an early and potent activation of PKC-alpha and a late decrease of PKB activity. ApoE4 and Abeta(1-42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and Abeta(1-42)-induced early activation of GSK-3beta could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3beta through activation of upstream kinases likely compensates the effects of apoE4 and Abeta(1-42) on GSK-3beta, the unbalanced regulation of which may contribute to AD pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / chemistry
  • Apolipoproteins E / pharmacology*
  • Calcium / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Culture Media, Serum-Free / chemistry
  • Cytoskeletal Proteins / metabolism
  • Enzyme Activation / drug effects
  • Glycogen Synthase Kinase 3 / chemistry
  • Glycogen Synthase Kinase 3 / drug effects*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Neuroblastoma / chemistry
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Peptide Fragments / pharmacology*
  • Phosphorylation / drug effects
  • Protein Isoforms / chemistry
  • Protein Isoforms / pharmacology
  • Protein Kinase C / drug effects
  • Protein Kinase C / metabolism
  • Protein Kinase C-alpha
  • Protein Serine-Threonine Kinases*
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Trans-Activators / metabolism
  • beta Catenin

Substances

  • Amyloid beta-Peptides
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E
  • CTNNB1 protein, human
  • Culture Media, Serum-Free
  • Cytoskeletal Proteins
  • Peptide Fragments
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Trans-Activators
  • amyloid beta-protein (1-42)
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PRKCA protein, human
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Glycogen Synthase Kinase 3
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Calcium