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JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease
Author(s) -
Zhu Xiongwei,
Ogawa Osamu,
Wang Yang,
Perry George,
Smith Mark A.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01645.x
Subject(s) - pathogenesis , senile plaques , alzheimer's disease , kinase , activator (genetics) , neuroscience , disease , medicine , pathology , biology , microbiology and biotechnology , endocrinology , receptor
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.