Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease

Neuromolecular Med. 2013 Sep;15(3):458-69. doi: 10.1007/s12017-013-8232-3. Epub 2013 May 12.

Abstract

The microtubule-affinity regulating kinase (MARK) family consists of four highly conserved members that have been implicated in phosphorylation of tau protein, causing formation of neurofibrillary tangles in Alzheimer's disease (AD). Understanding of roles by individual MARK isoform in phosphorylating tau has been limited due to lack of antibodies selective for each MARK isoform. In this study, we first applied the proximity ligation assay on cells to select antibodies specific for each MARK isoform. In cells, a CagA peptide specifically and significantly inhibited tau phosphorylation at Ser²⁶² mediated by MARK4 but not other MARK isoforms. We then used these antibodies to study expression levels of MARK isoforms and interactions between tau and individual MARK isoforms in postmortem human brains. We found a strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains, correlating with the Braak stages of the disease. These results suggest the MARK4-tau interactions are of functional importance in the progression of AD and the results also identify MARK4 as a promising target for AD therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Animals
  • Antibody Specificity
  • Antigens, Bacterial / chemistry
  • Bacterial Proteins / chemistry
  • Brain / enzymology
  • Disease Progression
  • Female
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / immunology
  • Nerve Tissue Proteins / physiology*
  • Neurofibrillary Tangles / metabolism
  • Peptide Fragments / pharmacology
  • Phosphorylation
  • Phosphoserine / analysis
  • Protein Interaction Mapping
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / immunology
  • Protein Isoforms / physiology
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / physiology*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • tau Proteins / metabolism*

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • MAPT protein, human
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Protein Isoforms
  • Recombinant Fusion Proteins
  • cagA protein, Helicobacter pylori
  • tau Proteins
  • Phosphoserine
  • MARK4 protein, human
  • Protein-Serine-Threonine Kinases