Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples
Open accessAbstract
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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Short peptides with altered amino acid sequences that target cross-sectional interfaces have been successfully employed in capping of various amyloid fibrils and inhibition of seeding.
“Notably, short peptides with altered amino acid sequences that target the cross-sectional interfaces of aggregation-prone regions have been successfully employed in the capping of various amyloid fibrils and the inhibition of seeding (63, 64, 65, 66).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [63]
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Why amyloid fibrils have a limited widthPreprint
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Simulations of Amyloid-Forming Peptides in the Crystal State
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Cellular toxicity of scrapie prions in prion diseases; a biochemical and molecular overview
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Genetic and structural aspects of amyloid diseases
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Self-citationStructural evidence that RNA contributes to polymorphism of tau amyloid fibrils
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Hurdles and Strategies in Treating Alzheimer’s Disease
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Contribution of G4 Structure to Alzheimer’s Disease and Tau Pathology
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- Authors
- Seidler, P. M., Boyer, D. R., Murray, K. A., Yang, T. P., Bentzel, M., Sawaya, M. R., Rosenberg, G., Cascio, D., Williams, C. K., Newell, K. L., Ghetti, B., DeTure, M. A., Dickson, D. W., Vinters, H. V., & Eisenberg, D. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Indiana University School of Medicine (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Eisenberg, David S.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 294
- Issue
- 44
- Pages
- 16451-16464
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6827308
- OpenAlex
- W2974790801
- Cited by
- 70
- References
- 32
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 13 · 2021: 20 · 2020: 7
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- Funders
- HHS | NIH | National Institute on Aging (RF1 AG054022, PHS P30-AG010133, 1R01 AG061847)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (1F32 NS095661)
- BrightFocus Foundation (A2016588F)
- HHS | U.S. Public Health Service (5T32GM008496)
- National Science Foundation (GRFP)
- Topics
- Health Sciences › Medicine › Physiology › 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 aggregation, prion-like seeding, Alzheimer's disease, tauopathy, peptide inhibitors, progressive supranuclear palsy, neurodegeneration
- MeSH terms
- Alzheimer Disease, Brain, Humans, Neurons, Prions, tau Proteins, Tauopathies, HEK293 Cells, Protein Aggregation, Pathological
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