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Trans-cellular Propagation of Tau Aggregation by Fibrillar Species
Open accessAbstract
Aggregation of the microtubule associated protein Tau is associated with several neurodegenerative disorders, including Alzheimer disease and frontotemporal dementia. In Alzheimer disease, Tau pathology spreads progressively throughout the brain, possibly along existing neural networks. However, it is still unclear how the propagation of Tau misfolding occurs. Intriguingly, in animal models, vaccine-based therapies have reduced Tau and synuclein pathology by uncertain mechanisms, given that these proteins are intracellular. We have previously speculated that trans-cellular propagation of misfolding could be mediated by a process similar to prion pathogenesis, in which fibrillar Tau aggregates spread pathology from cell to cell. However, there has been little evidence to demonstrate true trans-cellular propagation of Tau misfolding, in which Tau aggregates from one cell directly contact Tau protein in the recipient cell to trigger further aggregation. Here we have observed that intracellular Tau fibrils are directly released into the medium and then taken up by co-cultured cells. Internalized Tau aggregates induce fibrillization of intracellular Tau in these naive recipient cells via direct protein-protein contact that we demonstrate using FRET. Tau aggregation can be amplified across several generations of cells. An anti-Tau monoclonal antibody blocks Tau aggregate propagation by trapping fibrils in the extracellular space and preventing their uptake. Thus, propagation of Tau protein misfolding among cells can be mediated by release and subsequent uptake of fibrils that directly contact native protein in recipient cells. These results support the model of aggregate propagation by templated conformational change and suggest a mechanism for vaccine-based therapies in neurodegenerative diseases.
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“In cell culture, C2N-8E12 prevented pathological tau seeding caused by exogenous tau aggregates212.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [212]
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Metadata
- Authors
- Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M., & Diamond, M. I.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Diamond, Marc I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 287
- Issue
- 23
- Pages
- 19440-19451
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3365982
- OpenAlex
- W2032355167
- Cited by
- 552
- References
- 43
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 18 · 2023: 29 · 2022: 34 · 2021: 51 · 2020: 47 · 2019: 59 · 2018: 48 · 2017: 46 · 2016: 41 · 2015: 41 · 2014: 47 · 2013: 43 · 2012: 15
- FWCI
- 31.29
- 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
- American Health Assistance Foundation
- Ruth K. Broad Biomedical Research Foundation
- Muscular Dystrophy Association
- Washington University in St. Louis
- Foundation for Barnes-Jewish Hospital
- Alvin J. Siteman Cancer Center
- Hope Center for Neurological Disorders
- National Institutes of Health (NS057105)
- Tau Consortium
- Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
- National Institute on Aging (P50AG005681)
- National Institute of Neurological Disorders and Stroke (F31NS079039, P30NS057105, NS057105, R01NS071835)
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau aggregation, Alzheimer's disease, frontotemporal dementia, protein misfolding, prion-like propagation, protein-protein contacts, neurodegenerative diseases
- MeSH terms
- Alzheimer Disease, Humans, Models, Biological, tau Proteins, Protein Folding, Multiprotein Complexes, Antibodies, Neutralizing, Frontotemporal Dementia, HEK293 Cells, Antibodies, Monoclonal, Murine-Derived
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