Cited by 17Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

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

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Berrocal, Maria, Caballero-Bermejo, Montaña, Gutierrez-Merino, Carlos, Mata, Ana M.·2019·International Journal of Molecular Sciences

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.

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  • Methylene blue was tried in Phase II clinical trials for mild-to-moderate AD for suppressing tau aggregation and has drawn criticism due to binding efficiency problems showing blue discolorations in urine.

    “Due to problems with binding efficiency, which show up as blue discolorations in urine, methylene blue (labeled as 12, Figure 5), which was also tried in Phase II clinical trials for mild-to-moderate AD (for suppressing tau aggregation), has drawn a lot of criticism [168,169,170].”

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Authors
Berrocal, M., Caballero-Bermejo, M., Gutierrez-Merino, C., & Mata, A. M.
Affiliations
  • Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura and Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, Spain
  • Universidad de Extremadura (ES)
Corresponding author
Mata, Ana M.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-07-18
Volume
20
Issue
14
Pages
3521
ISSN
1422-0067 (ISSN-L)
OpenAlex
W2956809851
Cited by
17
References
89
Citations by year
2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 1
FWCI
2.06
Type
journal article
Language
en
Open access
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repository University of Extremadura (University of Extremadura) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Ministerio de Economía y Competitividad (BFU2017-85723-P)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
methylene blue, tau protein, plasma membrane Ca2+-ATPase, Alzheimer's disease, calcium homeostasis, phenothiazines, amyloid-beta, tau toxicity, mechanism of action
MeSH terms
Animals, Brain, Calcium, Cell Membrane, Humans, Methylene Blue, Protein Binding, Swine, tau Proteins, Apoptosis, Reactive Oxygen Species, Cell Line, Tumor, Plasma Membrane Calcium-Transporting ATPases, In Vitro Techniques

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