Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation
Open accessAbstract
Alzheimer disease and several other neurodegenerative disorders are characterized by the accumulation of intraneuronal fibrils comprised of the protein Tau. Tau is normally a soluble protein that stabilizes microtubules, with splice isoforms that contain either three (3-R) or four (4-R) microtubule binding repeats. The formation of Tau fibrils is thought to result in neuronal damage, and inhibitors of Tau fibrillization may hold promise as therapeutic agents. The process of Tau fibrillization can be replicated in vitro, and a number of small molecules have been identified that inhibit Tau fibril formation. However, little is known about how these molecules affect Tau fibrillization. Here, we examined the mechanism by which the previously described aminothieno pyridazine (ATPZ) series of compounds inhibit Tau fibrillization. Active ATPZs were found to promote the oxidation of the two cysteine residues within 4-R Tau by a redox cycling mechanism, resulting in the formation of a disulfide-containing compact monomer that was refractory to fibrillization. Moreover, the ATPZs facilitated intermolecular disulfide formation between 3-R Tau monomers, leading to dimers that were capable of fibrillization. The ATPZs also caused cysteine oxidation in molecules unrelated to Tau. Interestingly, methylene blue, an inhibitor of Tau fibrillization under evaluation in Alzheimer disease clinical trials, caused a similar oxidation of cysteines in Tau and other molecules. These findings reveal that the ATPZs and methylene blue act by a mechanism that may affect their viability as potential therapeutic agents.
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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 Crowe et al., 2013
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- Authors
- Crowe, A., James, M. J., Lee, V. M.-Y., Smith, A. B., Trojanowski, J. Q., Ballatore, C., & Brunden, K. R.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Brunden, Kurt R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 288
- Issue
- 16
- Pages
- 11024-11037
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3630889
- OpenAlex
- W2054710865
- Cited by
- 143
- References
- 55
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 15 · 2021: 12 · 2020: 19 · 2019: 12 · 2018: 10 · 2017: 15 · 2016: 14 · 2015: 11 · 2014: 8 · 2013: 6
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG017586, AG17586)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- methylene blue, tau protein, tau fibrillization, cysteine oxidation, disulfide bond formation, redox cycling, Alzheimer's disease, microtubule-binding repeats, neurodegenerative diseases
- MeSH terms
- Alzheimer Disease, Cysteine, Humans, Methylene Blue, Oxidation-Reduction, tau Proteins, Multiprotein Complexes
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