Methylene Blue Blocks and Reverses the Inhibitory Effect of Tau on PMCA Function
Open accessAbstract
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].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [169]
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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)
- PMC
- PMC6678728
- 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
- gold
- dx.doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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