Cited by 300Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

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Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

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Congdon, Erin E., Wu, Jessica W., Myeku, Natura, Figueroa, Yvette H., Herman, Mathieu, Marinec, Paul S., Gestwicki, Jason E., Dickey, Chad A., Yu, W. Haung, Duff, Karen E.·2012·Autophagy

DOI 10.4161/auto.19048PMC PMC3405840

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Abstract

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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1 retracted

RETRACTED: Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade
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Retracted
p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death
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Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
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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: Congdon, Erin E.
Wu, Jessica W.
Myeku, Natura
Gestwicki, Jason E.
Dickey, Chad A.
Yu, W. Haung
Duff, Karen E.
Venue: Autophagy
Publisher: Informa UK Limited
Published: 2012-04
Volume: 8
Issue: 4
Pages: 609-622
ISSN: 1554-8627 (ISSN-L)
1554-8635
DOI: 10.4161/auto.19048
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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Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

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