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Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo
Open accessAbstract
More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubule-binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, BECN1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases.
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“Any putative benefit attributed to methylene blue has been thought to be secondary to reduced tau fibrillization and aggregation and induction of autophagy, which leads to reduced tau pathology and neuron death in mouse models of tauopathy (Congdon et al., 2012; Crowe et al., 2013; Wischik et al., 1996).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Congdon et al., 2012
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Metadata
- Authors
- Congdon, E. E., Wu, J. W., Myeku, N., Figueroa, Y. H., Herman, M., Marinec, P. S., Gestwicki, J. E., Dickey, C. A., Yu, W. H., & Duff, K. E.
- Affiliations
- New York State Psychiatric Institute (US)
- University of Michigan (US)
- University of South Florida (US)
- Corresponding author
- Duff, Karen E.
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2012-04
- Volume
- 8
- Issue
- 4
- Pages
- 609-622
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC3405840
- OpenAlex
- W2090455820
- Cited by
- 297
- References
- 49
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 16 · 2023: 10 · 2022: 21 · 2021: 29 · 2020: 37 · 2019: 14 · 2018: 16 · 2017: 23 · 2016: 27 · 2015: 26 · 2014: 25 · 2013: 23 · 2012: 10
- FWCI
- 18.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Health Assistance Foundation
- Alzheimer's Drug Discovery Foundation
- National Institutes of Health
- National Institute on Aging (R00AG031291)
- National Institute of Neurological Disorders and Stroke (R01NS074593, NS074593, R01NS073899)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- methylene blue, tauopathy, tau aggregation, neurofibrillary tangles, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, LC3-II, cathepsin D, Beclin-1, p62, neurodegenerative disease treatment, organotypic brain slice culture
- MeSH terms
- Animals, Autophagy, Brain, Cells, Cultured, Cricetinae, Humans, Lysosomes, Methylene Blue, Mice, Transgenic, Microtubule-Associated Proteins, Models, Biological, Neurons, Phosphorylation, Vacuoles, Biomarkers, CHO Cells, tau Proteins, Protein Transport, Tauopathies, Mice, Gene Knockdown Techniques
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