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
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“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
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“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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Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
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
Cells release prions in association with exosomes
Février, B., Vilette, D., Archer, F., Loew, D., Faigle, W., Vidal, M., Laude, H., & Raposo, G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308413101 · Cited by 998
Goedert, M., & Jakes, R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07870.x · Cited by 929
Kayed, R., Sokolov, Y., Edmonds, B. W., McIntire, T. M., Milton, S. C. F., Hall, J. E., & Glabe, C. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400260200 · Cited by 913
The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease.
Delacourte, A., David, J. P., Sergeant, N., Buée, L., Wattez, A., Vermersch, P., Ghozali, F., Fallet-Bianco, C., Pasquier, F., Lebert, F., et al. (1999) · Neurology · doi:10.1212/wnl.52.6.1158 · Cited by 828
Greenberg, S. G., & Davies, P. J. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.15.5827 · Cited by 735
Asuni, A. A., Boutajangout, A., Quartermain, D., & Sigurdsson, E. M. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2361-07.2007 · Cited by 506
Vandermeeren, M., Mercken, M. H., Vanmechelen, E., Six, J., VOORDE, A. V. D., Martin, J., & Cras, P. P. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb09823.x · Cited by 496
Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates
Ren, P.-H., Lauckner, J. E., Kachirskaia, I., Heuser, J. E., Melki, R., & Kopito, R. R. (2009) · Nature Cell Biology · doi:10.1038/ncb1830 · Cited by 427
Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells
Yang, W. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.23.2905 · Cited by 379
Ryder, E. F., Snyder, E. Y., & Cepko, C. L. (1990) · Journal of Neurobiology · doi:10.1002/neu.480210209 · Cited by 365
Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules.
Trinczek, B., Biernat, J., Baumann, K., Mandelkow, E. M., & Mandelkow, E. (1995) · Molecular Biology of the Cell · doi:10.1091/mbc.6.12.1887 · Cited by 340
A nucleated assembly mechanism of Alzheimer paired helical filaments
Friedhoff, P., von Bergen�, M., Mandelkow�, E., Davies, P., & Mandelkow�, E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15712 · Cited by 340
Behavioral disorders in the frontal and temporal variants of frontotemporal dementia
Liu, W., Miller, B. L., Kramer, J. H., Rankin, K., Wyss-Coray, C., Gearhart, R., Phengrasamy, L., Weiner, M., & Rosen, H. J. (2004) · Neurology · doi:10.1212/01.wnl.0000113729.77161.c9 · Cited by 313
Neurofibrillary Degeneration in Progressive Supranuclear Palsy and Corticobasal Degeneration
Sergeant, N., Wattez, A., & Delacourte, A. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0721243.x · Cited by 301
Gómez‐Ramos, A., Dı́az-Hernández, M., Rubio, A., Miras‐Portugal, M. T., & Ávila, J. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.12.010 · Cited by 245
Extracellular tau is toxic to neuronal cells
Gómez-Ramos, A., Díaz-Hernández, M., Cuadros, R., Hernández, F., & Avila, J. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.07.078 · Cited by 241
Conformational Diversity of Wild-type Tau Fibrils Specified by Templated Conformation Change
Frost, B., Ollesch, J., Wille, H., & Diamond, M. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m805627200 · Cited by 224
Self-citationTau-dependent microtubule disassembly initiated by prefibrillar β-amyloid
King, M. E., Kan, H.-M., Baas, P. W., Erişir, A., Glabe, C. G., & Bloom, G. S. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200605187 · Cited by 215
Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells
Magalhães, A. C., Baron, G. S., Lee, K. S., Steele‐Mortimer, O., Dorward, D. W., Prado, M. A. M., & Caughey, B. W. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0653-05.2005 · Cited by 158
Transfer of Scrapie Prion Infectivity by Cell Contact in Culture
Kanu, N., Imokawa, Y., Drechsel, D. N., Williamson, R. A., Birkett, C. R., Bostock, C. J., & Brockes, J. P. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00722-4 · Cited by 135
Origins and kinetic consequences of diversity in Sup35 yeast prion fibers
DePace, A. H., & Weissman, J. S. (2002) · Nature Structural Biology · doi:10.1038/nsb786 · Cited by 119
Lack of the car☐yl terminal sequence of tau in ghost tangles of Alzheimer's disease
Endoh, R., OGAWARA, M., Iwatsubo, T., Nakano, I., & Mori, H. (1993) · Brain Research · doi:10.1016/0006-8993(93)91707-y · Cited by 87
Flagged first, then by citations
Research works printed but not linked: 2
- Delacourte, 2005, Polish Acad. Sci., 43, 244
- DePace, 2002, Nat. Struct. Biol., 9, 389
Cited by
Sorted by citations
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708
Bloom (2014) · doi:10.1001/jamaneurol.2013.5847 · Cited by 2,194
The spectrum of disease in chronic traumatic encephalopathy
McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., Lee, H.-S., Hall, G., Wojtowicz, S. M., Baugh, C. M., et al. (2013) · Brain · doi:10.1093/brain/aws307 · Cited by 2,098
The glymphatic system: a beginner's guide
Jessen, N. A., Munk, A. S. F., Lundgaard, I., & Nedergaard, M. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1581-6 · Cited by 2,075
Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050
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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