In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta

J Neurochem. 1996 Aug;67(2):699-707. doi: 10.1046/j.1471-4159.1996.67020699.x.


The two pathological lesions found in the brains of Alzheimer's disease patients, neurofibrillary tangles and neuritic plaques, are likely to be formed through a common pathway. Neurofibrillary tangles are intracellular aggregates of paired helical filaments, the main component of which is hyperphosphorylated forms of the microtubule-associated protein tau. Extracellular neuritic plaques and diffuse and vascular amyloid deposits are aggregates of beta-amyloid protein, a 4-kDa protein derived from the amyloid precursor protein (APP). Using conditions in vitro under which two proline-directed protein kinases, glycogen synthase kinase-3beta (GSK-3beta) and mitogen-activated protein kinase (MAPK), were able to hyperphosphorylate tau, GSK-3beta but not MAPK phosphorylated recombinant APPcyt. The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). This site was confirmed by endoproteinase Glu-C digestion of APPcyt and peptide sequencing. The ability of GSK-3beta to phosphorylate APPcyt and tau provides a putative link between the two lesions and indicates a critical role of GSK-3beta in the pathogenesis of Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cytoplasm / metabolism
  • DNA Primers / chemistry
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Mitogen-Activated Protein Kinase 1
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Rats


  • Amyloid beta-Protein Precursor
  • DNA Primers
  • Phosphothreonine
  • Protein-Tyrosine Kinases
  • Glycogen Synthase Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Glycogen Synthase Kinase 3