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

Cellular responses to increased oxidative stress appear to be a mechanism t hat contributes to the varied cytopathology of Alzheimer's disease (AD). in this regard, we suspect that c-Jun N-terminal kinase/Stress activated prot ein kinase (JNK/SAPK), a major cellular stress response protein induced by oxidative stress, plays an important role in Alzheimer disease in susceptib le neurons facing the dilemma of proliferation or death. We found that JNK2 /SAPK-alpha and JNK3/SAPK-beta were related to neurofibrillary pathology an d JNK1/SAP-K gamma related to Hirano bodies in cases of AD but were only we akly diffuse in the cytoplasm in all neurons in control cases and in non-in volved neurons in diseased brain. In this regard, in hippocampal and cortic al regions of individuals with severe AD, the activated phospho-JNK/ SAPK w as localized exclusively in association with neurofibrillar alterations inc luding neurofibrillary tangles, senile plaque neurites, neuropil threads an d granulovacuolar degeneration structures (GVD), completely overlapping wit h tau -positive neurofibrillary pathology, but was virtually absent in thes e brain regions in younger and age-matched controls without pathology. Howe ver, 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 fr om nuclei to cytoplasm, respectively, indicating that the activation and re -distribution of JNK/SAPK correlates with the progress of the disease. By i mmunoblot 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.