JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease

J Neurochem. 2003 Apr;85(1):87-93. doi: 10.1046/j.1471-4159.2003.01645.x.


JNK/SAPK has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to JNK/SAPK activation has not been elucidated in the disease. In this study, we focused on one of the physiological activators of JNK/SAPK, JNK kinase 1 (JKK1). Although there was no significant difference in the level and distribution of total JKK1 between Alzheimer's disease (AD) and age-matched control cases, increased levels of activated phospho-JKK1 were specifically localized to neurofibrillary pathology including neurofibrillary tangles, senile plaque neurites, granulovaualar degenerations and neuropil threads in severe AD (Braak stage V-VI), considerably overlapping with its downstream effector, phospho-JNK/SAPK, suggesting both a functional and mechanistic link. Nuclear localization of phospho-JKK1 was also found in mild (Braak stage III-IV) but not in severe AD cases (Braak stage V-VI), suggesting a possible re-distribution correlating with the progress of the disease. By immunoblot analyses, phospho-JKK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the JNK/SAPK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / pathology*
  • Cell Nucleus / enzymology
  • Cell Nucleus / pathology
  • Cerebral Cortex / enzymology
  • Disease Progression
  • Enzyme Activation
  • Hippocampus / enzymology
  • Hippocampus / pathology
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurofibrillary Tangles / enzymology
  • Neurofibrillary Tangles / pathology


  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases