Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease
Abstract
Alzheimer’s disease pathology is characterized by extracellular deposits of amyloid-β (Aβ) and intracellular inclusions of hyperphosphorylated tau. Although genetic studies of familial Alzheimer’s disease suggest a causal link between Aβ and disease symptoms, the failure of various Aβ-targeted strategies to slow or halt disease progression has led to consideration of the idea that inhibition of tau aggregation might be a more promising therapeutic approach. Methylene blue (MB), which inhibits tau aggregation and rescue memory deficits in a mouse model of tauopathy, however, lacked efficacy in a recent Phase III clinical trial. In order to gain insight into this failure, the present study was designed to examine the mechanism through which MB inhibits tau aggregation. We found that MB inhibits heparin-induced tau aggregation in vitro, as measured by thioflavin T fluorescence. Further, MB reduced the amount of tau in precipitants recovered after ultracentrifugation of the aggregation mixture. Atomic force microscopy revealed that MB reduces the number of tau fibrils but increases the number of granular tau oligomers. The latter result was confirmed by sucrose gradient centrifugation: MB treatment was associated with higher levels of granular tau oligomers (fraction 3) and lower levels of tau fibrils (fractions 5 and 6). We previously demonstrated that the formation of granular tau oligomers, rather than tau fibrils, is essential for neuronal death. Thus, the fact that MB actions are limited to inhibition of tau fibril formation provides a mechanistic explanation for the poor performance of MB in the recent Phase III clinical trial.
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Methylene blue may increase granular tau oligomers which may trigger neuronal death, despite reducing tau fibril formation.
“A possible explanation for this may be derived from effects of methylene blue on increasing granular tau oligomers which may trigger neuronal death, despite concurrent effects in reducing tau fibril formation [649].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [649]
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 [168]
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- Authors
- Soeda, Y., Saito, M., Maeda, S., Ishida, K., Nakamura, A., Kojima, S., & Takashima, A.
- Affiliations
- Gakushuin University (JP)
- Keio University (JP)
- Corresponding author
- Takashima, Akihiko
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2019-03-18
- Volume
- 68
- Issue
- 4
- Pages
- 1677-1686
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2924805160
- Cited by
- 84
- References
- 51
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 14 · 2022: 12 · 2021: 17 · 2020: 13 · 2019: 3
- FWCI
- 7.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (18H05414, 17H07087, 26117004)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- methylene blue, tau aggregation
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Methylene Blue, Phosphorylation, Neurofibrillary Tangles, tau Proteins, Mice
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