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


Year of Publication:
Contact PI Name:
Karen E. Duff
Contact PI Affiliation:
Taub Institute/Department of Pathology, Columbia University and Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York, USA
Erin E. Congdon, Jessica W. Wu, Natura Myeku, Yvette H. Figueroa, Mathieu Herman, Paul S. Marinec, Jason E. Gestwicki, W. Haung Yu
Primary Reference (PubMED ID):
Funding Source:
American Health Assistance Foundation
National Institute of Neurological Disorders and Stroke (NINDS)
Alzheimer's Drug Discovery Foundation (ADDF)
Study Goal and Principal Findings:

The microtubule-binding protein tau is associated with pathology development and cellular dysfunction in more than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD). These diseases are pathologically charaterized, in part, by the accumulation of an aggregated form of the microtubule binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. 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. In this study the authors 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  the JNPL3 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Methylthioninium Chloride (MTC)
Therapeutic Target:
Amyloidogenic Proteins

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Swiss Webster

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Total Tau Protein
Insoluble Tau
p70 S6 Kinase
Glycogen Synthase Kinase 3 beta (GSK3 beta)
Protein Kinase B (Akt/PKB)
Mechanistic Target of Rapamycin (mTOR)
Autophagic Vesicles
Drug Concentration-Brain
Cell Biology
Autophagic Markers
Outcomes Notes:
The authors also observed an improvement in cognitive performance after administration of MB, in the same tau transgenic mouse line used in this study and published in: O’Leary JC, III, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, et al. Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 2010; 5:45; PMID:21040568;