Tau phosphorylation in Alzheimer's disease: Potential involvement of an APP-MAP kinase complex

Alyson L. Peel, Noah Sorscher, Joseph Y. Kim, Veronica Galvan, Sylvia Chent, Dale E. Bredesen

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (β-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by β-amyloid peptide (Aβ) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Aβ peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.

Original languageEnglish (US)
Pages (from-to)205-218
Number of pages14
JournalNeuroMolecular Medicine
Volume5
Issue number3
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Keywords

  • MKK6
  • Mitogen-associated protein kinase
  • Neurodegeneration
  • Neurofibrillary tangle
  • PHF
  • Senile plaque
  • Stress-associated protein kinase
  • p38 MAPK

ASJC Scopus subject areas

  • Molecular Medicine
  • Neurology
  • Cellular and Molecular Neuroscience

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