Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.
Open accessAbstract
In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases. We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases. We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain. Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have Ki values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain. Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.
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Any putative benefit of methylene blue has been thought secondary to reduced tau fibrillization and aggregation and induction of autophagy, leading to reduced tau pathology and neuron death in mouse tauopathy models.
“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 Wischik et al., 1996
Methylene blue blocks the polymerization of tau in vitro by trapping tau monomers in an aggregation-incompetent conformation.
“Methylene blue blocks the polymerization of tau in vitro by trapping the tau monomers in an aggregation-incompetent conformation137,138.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [138]
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“Because tau is a component of microtubules and hyperphosphorylation of tau results in microtubule destabilization and resulting cytoskeleton degeneration, other agents of interest in AD are agents with microtubule stabilizing effects (99).”
BackgroundMethylene Blue Blocks and Reverses the Inhibitory Effect of Tau on PMCA Function
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- Authors
- Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M., & Harrington, C. R.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- University of Cambridge (GB)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1996-10
- Volume
- 93
- Issue
- 20
- Pages
- 11213-11218
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC38310
- OpenAlex
- W2167818155
- Cited by
- 547
- References
- 43
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 18 · 2023: 21 · 2022: 25 · 2021: 38 · 2020: 41 · 2019: 35 · 2018: 31 · 2017: 36 · 2016: 30 · 2015: 25 · 2014: 34 · 2013: 36 · 2012: 31
- FWCI
- 0.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, tau protein, tau aggregation, phenothiazines, methylene blue, paired helical filaments, neurofibrillary tangles, repeat domain, aggregation inhibitors, antipsychotic drugs
- MeSH terms
- Alzheimer Disease, Humans, Methylene Blue, Peptide Fragments, Phenothiazines, Pronase, Protein Binding, tau Proteins, Macromolecular Substances
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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