Role of protein kinase B in Alzheimer's neurofibrillary pathology

Acta Neuropathol. 2003 Apr;105(4):381-92. doi: 10.1007/s00401-002-0657-y. Epub 2002 Dec 18.

Abstract

Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / pathology
  • Blotting, Western
  • Brain / enzymology*
  • Brain / pathology
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Huntington Disease / enzymology
  • Huntington Disease / pathology
  • Immunohistochemistry
  • Isoenzymes / metabolism
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Neurofibrillary Tangles / enzymology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • tau Proteins / metabolism

Substances

  • Isoenzymes
  • Proto-Oncogene Proteins
  • tau Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3