title: Activation of MKK6, an upstream activator of p38, in Alzheimer's disease.
abstract: Mitogen-activated protein kinase (MAPK) p38 has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to p38 activation has not been elucidated in the disease. In the present study, we focused on mitogen-activated protein kinase kinase 6 (MKK6), one of the upstream activators of p38 MAPK. We found that MKK6 was not only increased but also specifically associated with granular structures in the susceptible neurons in the hippocampus and cortex of Alzheimer's disease patients, but was only weakly diffuse in the cytoplasm in neurons in control cases. Immunoblot analysis demonstrated a significant increase of MKK6 level in Alzheimer's disease compared with age-matched controls. In this regard, in hippocampal and cortical regions of individuals with Alzheimer's disease, the activated phospho-MKK6 was localized exclusively in association with pathological alterations including neurofibrillary tangles, senile plaques, neuropil threads and granular structures, overlapping with activated p38 MAPK suggesting both a functional and mechanic link. By immunoblot analysis, phospho-MKK6 is also significantly increased in AD compared with control cases. Together, these findings lend further credence to the notion that the p38 MAPK pathway is dysregulated in Alzheimer's disease and also indicates an active role for this pathway in disease pathogenesis.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: C A
authors.initials: CA
authors.lastname: Rottkamp
authors.forename: A
authors.initials: A
authors.lastname: Hartzler
authors.forename: Z
authors.initials: Z
authors.lastname: Sun
authors.forename: A
authors.initials: A
authors.lastname: Takeda
authors.forename: H
authors.initials: H
authors.lastname: Boux
authors.forename: S
authors.initials: S
authors.lastname: Shimohama
authors.forename: G
authors.initials: G
authors.lastname: Perry
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002675:Child, Preschool; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D048669:MAP Kinase Kinase 6; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014018:Tissue Distribution; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human