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.
“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
The Abstract and Discussion report that extracellular tau aggregates seed intracellular tau misfolding and that newly aggregated tau transfers between co-cultured cells. The Discussion says it remains uncertain whether transferred aggregates induce further aggregation in recipient cells; the study also does not demonstrate that toxicity spreads between cells. The claim presents those steps as an established mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTau propagates pathology among neurons.
“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
The Abstract reports Tau-induced misfolding and transfer of aggregated Tau between co-cultured cells. The Discussion says these findings are consistent with propagation among neurons, but explicitly says that this idea awaits testing in vivo. The paper therefore supports evidence for a possible mechanism, not a demonstrated spread of pathology among neurons. (LLM, conf=0.85)
Experimental — accuracy not yet measuredProteopathic tau seeds are capable of entering a cell and promoting aggregation in a prion-like manner.
“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
Tau assemblies enter cells to trigger intracellular aggregation.
“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
Aggregation of tau impairs axons, leading to neurodegeneration.
“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]
The current clinical trial literature is compatible with the idea that AβP-related substances kindle a self-propagating process related to neocortical NFTs.
“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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- 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
- Health Sciences › Medicine › Physiology › 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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