Methylene Blue Blocks and Reverses the Inhibitory Effect of Tau on PMCA Function.

Maria Berrocal,Carlos Gutierrez-Merino,Montaña Caballero-Bermejo,Ana M Mata

doi:10.3390/ijms20143521

Maria Berrocal, Carlos Gutierrez-Merino + Show 2 more

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https://doi.org/10.3390/ijms20143521

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Abstract

Methylene blue (MB) is a synthetic phenothiazine dye that, in the last years, has generated much debate about whether it could be a useful therapeutic drug for tau-related pathologies, such as Alzheimer’s disease (AD). However, the molecular mechanism of action is far from clear. Recently we reported that MB activates the plasma membrane Ca2+-ATPase (PMCA) in membranes from human and pig tissues and from cells cultures, and that it could protect against inactivation of PMCA by amyloid β-peptide (Aβ). The purpose of the present study is to further examine whether the MB could also modulate the inhibitory effect of tau, another key molecular marker of AD, on PMCA activity. By using kinetic assays in membranes from several tissues and cell cultures, we found that this phenothiazine was able to block and even to completely reverse the inhibitory effect of tau on PMCA. The results of this work point out that MB could mediate the toxic effect of tau related to the deregulation of calcium homeostasis by blocking the impairment of PMCA activity by tau. We then could conclude that MB could interfere with the toxic effects of tau by restoring the function of PMCA pump as a fine tuner of calcium homeostasis.

Highlights

Methylene blue (MB) is a thiophenazine dye, which has been extensively used in a wide range of applications, including as a bacteriological stain, as a redox analytical indicator, or as an antiseptic to treat several infections
We have shown that the plasma membrane Ca2+-ATPase (PMCA) seems to be involved in Ca2+ dysregulation associated with Alzheimer’s disease (AD), because it is functionally inhibited by both amyloid β-peptide (Aβ) and tau [31,32]
In this paper we report on our progress so far on the beneficial action of MB on the functional alteration of PMCA protein by molecular markers of AD

Summary

Introduction

Methylene blue (MB) is a thiophenazine dye, which has been extensively used in a wide range of applications, including as a bacteriological stain, as a redox analytical indicator, or as an antiseptic to treat several infections. AD is a neurodegenerative disease characterized by a loss of neuronal synapses and progressive cognitive decline that is reaching epidemic proportions in an increasingly aging world population [15] This explains the huge interest that exists to develop effective drugs to treat it. The presence of extracellular plaque deposits of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles (NFT) of tau protein are neuropathological hallmarks of neurodegeneration in AD [16,17,18] On these grounds, the studies on the molecular mechanisms underlying the beneficial effect of MB in AD have mainly been focused on its role in preventing aggregation of several neurodegenerative proteins, including tau [19,20], and repairing mitochondrial dysfunction [21,22,23,24]. As noted in Berrocal et al [35], this effect of MB is produced at micromolar concentrations, e.g., within the concentration range of MB reached in the nervous system in therapeutic bolus doses of MB, as shown in previous pharmacokinetic studies with rodents and humans [5,36,37]

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