ArticleThe Journal of biological chemistry2019
Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 66 citations in OpenAlex.
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- β-Bracelets: Macrocyclic Cross-β Epitope Mimics Based on a Tau Conformational Strain.Journal of the American Chemical Society · 2023Article
- Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- MAP2 caps tau fibrils and inhibits aggregation.The Journal of biological chemistry · 2023Article
- Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status.Molecules (Basel, Switzerland) · 2023Review
- Simulations of Amyloid-Forming Peptides in the Crystal State.The protein journal · 2023Article
- Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils.Nature communications · 2023Article
- Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?International journal of molecular sciences · 2022Review
- Electron Diffraction of 3D Molecular Crystals.Chemical reviews · 2022Review
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
In Alzheimer's disease (AD) and tauopathies, tau aggregation accompanies progressive neurodegeneration. Aggregated tau appears to spread between adjacent neurons and adjacent brain regions by prion-like seeding. Hence, inhibitors of this seeding offer a possible route to managing tauopathies. Here, we report the 1.0 Å resolution micro-electron diffraction structure of an aggregation-prone segment of tau with the sequence SVQIVY, present in the cores of patient-derived fibrils from AD and tauopathies. This structure illuminates how distinct interfaces of the parent segment, containing the sequence VQIVYK, foster the formation of distinct structures. Peptide-based fibril-capping inhibitors designed to target the two VQIVYK interfaces blocked proteopathic seeding by patient-derived fibrils. These VQIVYK inhibitors add to a panel of tau-capping inhibitors that targets specific polymorphs of recombinant and patient-derived tau fibrils. Inhibition of seeding initiated by brain tissue extracts differed among donors with different tauopathies, suggesting that particular fibril polymorphs of tau are associated with certain tauopathies. Donors with progressive supranuclear palsy exhibited more variation in inhibitor sensitivity, suggesting that fibrils from these donors were more polymorphic and potentially vary within individual donor brains. Our results suggest that a subset of inhibitors from our panel could be specific for particular disease-associated polymorphs, whereas inhibitors that blocked seeding by extracts from all of the tauopathies tested could be used to broadly inhibit seeding by multiple disease-specific tau polymorphs. Moreover, we show that tau-capping inhibitors can be transiently expressed in HEK293 tau biosensor cells, indicating that nucleic acid-based vectors can be used for inhibitor delivery.
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