JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease.
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.
Zhu
Xiongwei
X
Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. mas21@po.cwru.edu
Ogawa
Osamu
O
Wang
Yang
Y
Perry
George
G
Smith
Mark A
MA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D002540:Cerebral Cortex / Q000201:enzymology; D018450:Disease Progression; D004789:Enzyme Activation; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000473:pathology
D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases