Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment

Sci Rep. 2016 Oct 6;6:34784. doi: 10.1038/srep34784.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aβ-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Azure Stains / pharmacology
  • Drosophila Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Larva
  • Methylene Blue / pharmacology*
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Synapses / drug effects
  • Synapses / pathology
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Azure Stains
  • Drosophila Proteins
  • MAPT protein, human
  • tau Proteins
  • tau protein, Drosophila
  • MARK4 protein, human
  • Protein-Serine-Threonine Kinases
  • Azure C
  • Methylene Blue