Methylene Blue Reduced Abnormal Tau Accumulation in P301L Tau Transgenic Mice

Masato Hosokawa,Masami Masuda-Suzukake,Masato Hasegawa,Takashi Nonaka,Tetsuaki Arai,Haruhiko Akiyama,Makiko Yamashita,Andrea C Leblanc

doi:10.1371/journal.pone.0052389

Masato Hosokawa, Masami Masuda-Suzukake + Show 6 more

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https://doi.org/10.1371/journal.pone.0052389

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Abstract

In neurodegenerative disorders, abnormally hyperphosphorylated and aggregated tau accumulates intracellularly, a mechanism which is thought to induce neuronal cell death. Methylene blue, a type of phenothiazine, has been reported to inhibit tau aggregation in vitro. However, the effect of methylene blue in vivo has remained unknown. Therefore, we examined whether methylene blue suppresses abnormal tau accumulation using P301L tau transgenic mice. At 8 to 11 months of age, these mice were orally administered methylene blue for 5 months. Subsequent results of Western blotting analysis revealed that this agent reduced detergent-insoluble phospho-tau. Methylene blue may have potential as a drug candidate for the treatment of tauopathy.

Highlights

In neurodegenerative disorders such as Alzheimer’s disease, corticobasal degeneration, and supranuclear palsy, the microtubule–associated protein tau is abnormally phosphorylated and redistributed into paired helical filaments (PHFs) forming neurofibrillary tangles, a process that correlates with pyramidal cell destruction and dementia
We investigated whether MB could reduce abnormal tau accumulation by carrying out long-term oral administration of MB using tau transgenic mice with the P301L mutation as a tauopathy model
Immunoblotting Analysis To investigate the effect of methylene bule on tau accumulation, P301L tau transgenic mice were administered MB for 5 months starting at 8–11 months of age

Summary

Introduction

In neurodegenerative disorders such as Alzheimer’s disease, corticobasal degeneration, and supranuclear palsy, the microtubule–associated protein tau is abnormally phosphorylated and redistributed into paired helical filaments (PHFs) forming neurofibrillary tangles, a process that correlates with pyramidal cell destruction and dementia. Phenothiazines, including methylthioninium chloride (methylene blue (MB)), polyphenols and porphyrins, inhibited heparin-induced tau filament formation in vitro [2]. Based on these results, tau aggregation inhibitors are considered to be strong candidates for the treatment of tauopathy. TauRx Pharmaceuticals recently announced the completion of MB phase II clinical trials. They conducted MB dosing and efficacy studies involving 321 people with mild to moderate Alzheimer’s disease. Over a 50-week period, the cognitive decline of those on the drug appeared to be 81% slower than those taking a placebo These results were presented at a conference [3] but have not been published. A large-scale phase III trial is in planning [4]

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