Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease

J Neurochem. 2001 Jan;76(2):435-41. doi: 10.1046/j.1471-4159.2001.00046.x.


Cellular responses to increased oxidative stress appear to be a mechanism that contributes to the varied cytopathology of Alzheimer's disease (AD). In this regard, we suspect that c-Jun N-terminal kinase/Stress activated protein kinase (JNK/SAPK), a major cellular stress response protein induced by oxidative stress, plays an important role in Alzheimer disease in susceptible neurons facing the dilemma of proliferation or death. We found that JNK2/SAPK-alpha and JNK3/SAPK-beta were related to neurofibrillary pathology and JNK1/SAP-Kgamma related to Hirano bodies in cases of AD but were only weakly diffuse in the cytoplasm in all neurons in control cases and in non-involved neurons in diseased brain. In this regard, in hippocampal and cortical regions of individuals with severe AD, the activated phospho-JNK/SAPK was localized exclusively in association with neurofibrillar alterations including neurofibrillary tangles, senile plaque neurites, neuropil threads and granulovacuolar degeneration structures (GVD), completely overlapping with tau-positive neurofibrillary pathology, but was virtually absent in these brain regions in younger and age-matched controls without pathology. However, in control patients with some pathology, as well as in mild AD cases, there was nuclear phospho-JNK/SAPK and translocation of phospho-JNK/SAPK from nuclei to cytoplasm, respectively, indicating that the activation and re-distribution of JNK/SAPK correlates with the progress of the disease. By immunoblot analysis, phospho-JNK/SAPK is significantly increased in AD over control cases. Together, these findings suggest that JNK/SAPK dysregulation, probably resulting from oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in AD.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / pathology
  • Antibody Specificity
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / pathology
  • Child
  • Enzyme Activation
  • Hippocampus / enzymology
  • Hippocampus / pathology
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Isoenzymes / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Middle Aged
  • Mitogen-Activated Protein Kinase 10
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurofibrillary Tangles / enzymology
  • Neurofibrillary Tangles / pathology
  • Neurons / enzymology*
  • Neurons / pathology
  • Oxidative Stress
  • Protein-Tyrosine Kinases / metabolism
  • tau Proteins / biosynthesis


  • Isoenzymes
  • tau Proteins
  • Mitogen-Activated Protein Kinase 10
  • Mitogen-Activated Protein Kinase 9
  • Protein-Tyrosine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases