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

Xiongwei Zhu, Catherine A. Rottkamp, Anthony Hartzler, Zheng Sun, Atsushi Takeda, Heather Boux, Shun Shimohama, George Perry, Mark A. Smith

Research output: Contribution to journalArticlepeer-review

137 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)311-318
Number of pages8
JournalJournal of neurochemistry
Issue number2
StatePublished - 2001
Externally publishedYes


  • Alzheimer's disease
  • Cell cycle
  • Mitogen-activated protein kinase kinase 6
  • Oxidative stress
  • P38

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry


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