Small Misfolded Tau Species Are Internalized via Bulk Endocytosis and Anterogradely and Retrogradely Transported in Neurons
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The accumulation of Tau into aggregates is associated with key pathological events in frontotemporal lobe degeneration (FTD-Tau) and Alzheimer disease (AD). Recent data have shown that misfolded Tau can be internalized by cells in vitro (Frost, B., Jacks, R. L., and Diamond, M. I. (2009) J. Biol. Chem. 284, 12845–12852) and propagate pathology in vivo (Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., and Tolnay, M. (2009) Nat. Cell Biol. 11, 909–913; Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., and Kayed, R. (2012) Sci. Rep. 2, 700). Here we show that recombinant Tau misfolds into low molecular weight (LMW) aggregates prior to assembly into fibrils, and both extracellular LMW Tau aggregates and short fibrils, but not monomers, long fibrils, nor long filaments purified from brain extract are taken up by neurons. Remarkably, misfolded Tau can be internalized at the somatodendritic compartment, or the axon terminals and it can be transported anterogradely, retrogradely, and can enhance tauopathy in vivo . The internalized Tau aggregates co-localize with dextran, a bulk-endocytosis marker, and with the endolysosomal compartments. Our findings demonstrate that exogenous Tau can be taken up by cells, uptake depends on both the conformation and size of the Tau aggregates and once inside cells, Tau can be transported. These data provide support for observations that tauopathy can spread trans-synaptically in vivo , via cell-to-cell transfer. Background: Exogenous, misfolded Tau can be internalized, but details of the mechanism are unknown. Results: Small misfolded Tau species are internalized through endocytosis, anterogradely and retrogradely transported. Conclusion: Tau uptake is dependent on conformation and size of aggregates, and regulated through endocytosis. Significance: Understanding the mechanism by which pathological Tau is internalized provides a foundation for therapeutic approaches targeting uptake and propagation of tauopathy.
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Several studies have suggested that oligomeric tau in soluble forms may be the most potent neurotoxic form.
“Although tau aggregates are hallmarks of AD, several studies have suggested that oligomeric tau in soluble forms may be the most potent neurotoxic form 68–73.”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [69]
The References section cites studies describing neurotoxic tau oligomers and oligomer-associated dysfunction. The Conformation-dependent Uptake and Transport section also reports that small tau oligomers are elevated in AD brains and precede tangles. Our copy does not establish that soluble oligomeric tau is the most potent neurotoxic form relative to other tau species. (LLM, conf=0.77)
Experimental — accuracy not yet measuredMicroglia readily take up both soluble and insoluble forms of tau.
“Microglia readily take up both soluble and insoluble forms of tau [7, 56, 82, 116].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [56]
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- Authors
- Wu, J. W., Herman, M., Liu, L., Simoes, S., Acker, C. M., Figueroa, H., Steinberg, J. I., Margittai, M., Kayed, R., Zurzolo, C., Di Paolo, G., & Duff, K. E.
- Affiliations
- Columbia University (US)
- Albert Einstein College of Medicine (US)
- University of Denver (US)
- The University of Texas Medical Branch at Galveston (US)
- Institut Pasteur (FR)
- New York State Psychiatric Institute (US)
- Corresponding author
- Duff, Karen E.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 288
- Issue
- 3
- Pages
- 1856-1870
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3548495
- OpenAlex
- W1995202691
- Cited by
- 537
- References
- 76
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 49 · 2023: 37 · 2022: 31 · 2021: 51 · 2020: 53 · 2019: 52 · 2018: 35 · 2017: 39 · 2016: 40 · 2015: 35 · 2014: 36 · 2013: 31
- FWCI
- 21.87
- 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)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- HAL (submittedVersion, other-oa)
- Funders
- American Health Assistance Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS076619, NS056049, NS074874, R01NS056049, R01NS074874, NS076619, R01NS081555)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- tau protein, tauopathy, tau misfolding, bulk endocytosis, anterograde transport, retrograde transport, axon terminals, tau spread, cell-to-cell transmission, tau fibrils, endolysosomes, frontotemporal lobar degeneration, Alzheimer's disease, neuronal uptake
- MeSH terms
- Alzheimer Disease, Animals, Biological Transport, Brain Chemistry, Dextrans, Endocytosis, Humans, Kinetics, Mice, Transgenic, Microscopy, Electron, Molecular Weight, Neurons, Protein Binding, Endosomes, Recombinant Proteins, Synaptic Vesicles, Biomarkers, tau Proteins, Protein Folding, Mice, Primary Cell Culture
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