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Cofactors are essential constituents of stable and seeding-active tau fibrils
Open accessAbstract
Amyloid fibrils are cross-β-rich aggregates that are exceptionally stable forms of protein assembly. Accumulation of tau amyloid fibrils is involved in many neurodegenerative diseases, including Alzheimer's disease (AD). Heparin-induced aggregates have been widely used and assumed to be a good tau amyloid fibril model for most biophysical studies. Here we show that mature fibrils made of 4R tau variants, prepared with heparin or RNA, spontaneously depolymerize and release monomers when their cofactors are removed. We demonstrate that the cross-β-sheet assembly formed in vitro with polyanion addition is unstable at room temperature. We furthermore demonstrate high seeding capacity with transgenic AD mouse brain-extracted tau fibrils in vitro that, however, is exhausted after one generation, while supplementation with RNA cofactors resulted in sustained seeding over multiple generations. We suggest that tau fibrils formed in brains are supported by unknown cofactors and inhere higher-quality packing, as reflected in a more distinct conformational arrangement in the mouse fibril-seeded, compared with heparin-induced, tau fibrils. Our study suggests that the role of cofactors in tauopathies is a worthy focus of future studies, as they may be viable targets for diagnosis and therapeutics.
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“anionic experimental cofactor models have been described to promote aggregation: heparin (Goedert et al., 1996; Fichou et al., 2018) and RNA or its associated granules (Kampers et al., 1996; Zhang et al., 2017; Dinkel et al., 2015).”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Fichou et al., 2018
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Metadata
- Authors
- Fichou, Y., Lin, Y., Rauch, J. N., Vigers, M., Zeng, Z., Srivastava, M., Keller, T. J., Freed, J. H., Kosik, K. S., & Han, S.
- Affiliations
- University of California, Santa Barbara (US)
- Cornell University (US)
- Corresponding author
- Fichou, Yann
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-12-11
- Volume
- 115
- Issue
- 52
- Pages
- 13234-13239
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6310788
- OpenAlex
- W2905087948
- Cited by
- 128
- References
- 37
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 12 · 2023: 14 · 2022: 19 · 2021: 24 · 2020: 14 · 2019: 10
- FWCI
- 8.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | National Institutes of Health (R01AG05605, P41GM103521)
- Tau consortium
- Rainwater foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, amyloid fibrils, cofactors, fibril seeding, Alzheimer's disease, tauopathy, 4R tau, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Brain, Heparin, Mice, Transgenic, Protein Conformation, Recombinant Proteins, RNA, tau Proteins, Mice
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