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Methylene blue activates the PMCA activity and cross-interacts with amyloid β-peptide, blocking Aβ-mediated PMCA

Maria Berrocal1, Isaac Corbacho1, Carlos Gutierrez-Merino1

  • 1Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura and Instituto Universitario de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, Badajoz 06006, Spain.

Neuropharmacology
|July 14, 2018
PubMed

Insights

Methylene blue (MB) may benefit Alzheimer's disease (AD) by stimulating plasma membrane Ca2+-ATPase (PMCA) activity. MB also prevents amyloid-beta (Aβ) from inhibiting PMCA, suggesting a novel therapeutic mechanism.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Alzheimer's disease (AD) involves amyloid-beta (Aβ) aggregation and calcium (Ca2+) dysregulation.
  • Methylene blue (MB) is a phenothiazine with potential therapeutic effects in AD pathogenesis.
  • The precise molecular mechanisms of MB's action in AD remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanism of methylene blue (MB) in Alzheimer's disease (AD).
  • To determine MB's effect on plasma membrane Ca2+-ATPase (PMCA) activity in the presence of amyloid-beta (Aβ).

Main Methods:

  • Assessed PMCA activity in human AD brain tissue, control brain tissue, pig brain, and cell cultures.
  • Utilized functional analysis with mutants and fluorescence experiments to study MB-PMCA interactions.
  • Investigated the influence of Aβ on PMCA activity and its interaction with MB.

Main Results:

  • MB was found to stimulate Ca2+-ATPase activity of PMCA in various brain tissues and cell cultures.
  • MB effectively prevented and inhibited the suppressive effect of Aβ on PMCA activity.
  • MB binds to the C-terminal tail of PMCA near the last transmembrane helix and also binds to Aβ.
  • Aβ was observed to enhance PMCA's affinity for MB.

Conclusions:

  • MB's beneficial effects in AD may stem from its interaction with PMCA, modulating Ca2+ homeostasis.
  • MB's ability to counteract Aβ inhibition of PMCA offers a novel therapeutic target for AD.
  • These findings elucidate a new molecular basis for MB's therapeutic potential in Alzheimer's disease.
Keywords:
AβMethylene blueMolecular interactionsNeuronal Ca2+ dysregulationPMCA

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