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

Abstract

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-a and JNK3/SAPK-b were related to neuro®brillary pathology and JNK1/SAP-Kg 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 neuro®brillar alterations including neuro®brillary tangles, senile plaque neurites, neuropil threads and granulovacuolar degeneration structures (GVD), completely overlapping with t-positive neuro®brillary 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 signi®cantly increased in AD over control cases. Together, these ®ndings suggest that JNK/SAPK dysregulation, probably resulting from oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in AD.

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

“…JNK activation and nuclear translocation in neurons have been reported in vivo under different pathological conditions. Nuclear localization of JNK has been detected in degenerating neurons of Alzheimer patients (Zhu et al, 2001) and in cerebellar granule neurons (Coffey et al, 2000(Coffey et al, , 2002. JNK1 and JNK3 translocation from the cytosol to the nucleus in neurons can also be observed in experimental models of hypoxia (Zhang et al, 1998) and ischemia (Mizukami et al, 1997) respectively.…”

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

“…brain shows phospho-JNK up-regulation (Zhu et al, 2001;Savage et al, 2002) prompted us to examine the levels of phospho-JNK, -ERK, -p38 MAPKs, and phospho-c-Jun in the Tg-hCTF99/B6 brain. It was found that the levels of phospho-JNK and phospho-c-Jun in the whole cerebrum homogenate of Tg-hCTF99/B6 at 15 months were notably higher than those of age-matched controls, whereas the expressions of JNK1, JNK2, JNK3, phospho-ERK, and phospho-p38 were not significantly changed (Fig.…”

The TAT-JNK inhibitor peptide interferes with beta amyloid protein stability

“…Activated JNK is significantly increased in AD and is localized in the cytoplasm of neurons, the pattern correlating with the progression of the disease. 17 However, the physiological functions of APP phosphorylation at Thr 668 in neurons remain largely unknown and some possible functions of APP may be clarified by studies of the AICD domain and its partners.…”