Activation of MKK6, an upstream activator of p38, in Alzheimer's disease

Mitogen-activated protein kinase (MAPK) p38 has been implicated in the path ogenesis of Alzheimer's disease, but the upstream cascade leading to p38 ac tivation has not been elucidated in the disease. In the present study, we f ocused on mitogen-activated protein kinase kinase 6 (MKK6), one of the upst ream activators of p38 MAPK. We found that MKK6 was not only increased but also specifically associated with granular structures in the susceptible ne urons in the hippocampus and cortex of Alzheimer's disease patients, but wa s only weakly diffuse in the cytoplasm in neurons in control cases. Immunob lot analysis demonstrated a significant increase of MKK6 level in Alzheimer 's disease compared with age-matched controls. In this regard, in hippocamp al and cortical regions of individuals with Alzheimer's disease, the activa ted phospho-MKK6 was localized exclusively in association with pathological alterations including neurofibrillary tangles, senile plaques, neuropil th reads and granular structures, overlapping with activated p38 MAPK suggesti ng both a functional and mechanic link. By immunoblot analysis, phospho-MKK 6 is also significantly increased in AD compared with control cases. Togeth er, these findings lend further credence to the notion that the p38 MAPK pa thway is dysregulated in Alzheimer's disease and also indicates an active r ole for this pathway in disease pathogenesis.