The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Propagation of Tau Misfolding from the Outside to the Inside of a Cell
Open accessAbstract
Tauopathies are neurodegenerative diseases characterized by aggregation of the microtubule-associated protein Tau in neurons and glia. Although Tau is normally considered an intracellular protein, Tau aggregates are observed in the extracellular space, and Tau peptide is readily detected in the cerebrospinal fluid of patients. Tau aggregation occurs in many diseases, including Alzheimer disease and frontotemporal dementia. Tau pathology begins in discrete, disease-specific regions but eventually involves much larger areas of the brain. It is unknown how this propagation of Tau misfolding occurs. We hypothesize that extracellular Tau aggregates can transmit a misfolded state from the outside to the inside of a cell, similar to prions. Here we show that extracellular Tau aggregates, but not monomer, are taken up by cultured cells. Internalized Tau aggregates displace tubulin, co-localize with dextran, a marker of fluid-phase endocytosis, and induce fibrillization of intracellular full-length Tau. These intracellular fibrils are competent to seed fibril formation of recombinant Tau monomer in vitro. Finally, we observed that newly aggregated intracellular Tau transfers between co-cultured cells. Our data indicate that Tau aggregates can propagate a fibrillar, misfolded state from the outside to the inside of a cell. This may have important implications for understanding how protein misfolding spreads through the brains of tauopathy patients, and it is potentially relevant to myriad neurodegenerative diseases associated with protein misfolding.
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“Pathogenic forms of tau spread toxicity between cells through a prion-like mechanism involving seeded conformational change (Colin et al. 2020, Frost et al. 2009).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Frost et al. 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Several lines of evidence indicate tau propagates pathology among neurons.”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Frost et al., 2009
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In the citing paper
“Proteopathic tau seeds are capable of entering a cell and promoting aggregation in a prion-like manner (Clavaguera et al., 2009; Frost et al., 2009).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Frost et al., 2009
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“Tau assemblies enter cells to trigger intracellular aggregation (Frost et al., 2009; Holmes et al., 2014)”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Frost et al., 2009
In the citing paper
“The aggregation of tau impairs the axons, leading to neurodegeneration [23].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [23]
In the citing paper
“The current clinical trial literature is compatible with the idea that AβP-related substances kindle a self-propagating process related to neocortical NFTs, as has been hypothesized (266-269).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [267]
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Cites
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Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998) · Nature · doi:10.1038/31508 · Cited by 3,498
A protein factor essential for microtubule assembly
Weingarten, M. D., Lockwood, A. H., Hwo, S. Y., & Kirschner, M. W. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.5.1858 · Cited by 3,089
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480
Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories
Braak, H., & Braak, E. (1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00056-0 · Cited by 1,656
Mutation in the tau gene in familial multiple system tauopathy with presenile dementia
Spillantini, M. G., Murrell, J. R., Goedert, M., Farlow, M. R., Klug, A., & Ghetti, B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7737 · Cited by 1,474
Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., & Van Hoesen, G. W. (1991) · Cerebral Cortex · doi:10.1093/cercor/1.1.103 · Cited by 1,380
Tau is a candidate gene for chromosome 17 frontotemporal dementia
Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., Andreadis, A., Wiederholt, W. C., Raskind, M., & Schellenberg, G. D. (1998) · Annals of Neurology · doi:10.1002/ana.410430617 · Cited by 1,374
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Research works printed but not linked: 2
- Delacourte, 2005, Polish Acad. Sci., 43, 244
- DePace, 2002, Nat. Struct. Biol., 9, 389
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Anti-tau antibodies targeting a conformation-dependent epitope selectively bind seeds
Hitt, B. D., Gupta, A., Singh, R., Yang, T., Beaver, J. D., Shang, P., White, C. L., Joachimiak, L. A., & Diamond, M. I. (2023) · doi:10.1101/2023.05.04.539475 · Cited by 15
Self-citation
Metadata
- Authors
- Frost, B., Jacks, R. L., & Diamond, M. I.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Diamond, Marc I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 284
- Issue
- 19
- Pages
- 12845-12852
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2676015
- OpenAlex
- W1989208474
- Cited by
- 1,252
- References
- 32
- Citations by year
- 2026: 34 · 2025: 71 · 2024: 76 · 2023: 78 · 2022: 72 · 2021: 96 · 2020: 97 · 2019: 70 · 2018: 67 · 2017: 76 · 2016: 67 · 2015: 83 · 2014: 78 · 2013: 89 · 2012: 81
- FWCI
- 43.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- National Institutes of Health
- University of California, San Francisco
- National Institute of Neurological Disorders and Stroke (R01NS050284, R01 NS50284-03)
- 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
- tauopathy, prion-like propagation, fluid-phase endocytosis, Alzheimer's disease, frontotemporal dementia
- MeSH terms
- Animals, Animals, Newborn, Cell Line, Dextrans, Extracellular Space, Flow Cytometry, Fluorescent Antibody Technique, Humans, Kidney, Luminescent Proteins, Neurons, Stem Cells, Blotting, Western, tau Proteins, Protein Folding, Microscopy, Atomic Force, Coculture Techniques, Intracellular Space, Mice
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