Extracellular Monomeric Tau Protein Is Sufficient to Initiate the Spread of Tau Protein Pathology
Open accessAbstract
Understanding the formation and propagation of aggregates of the Alzheimer disease-associated Tau protein in vivo is vital for the development of therapeutics for this devastating disorder. Using our recently developed live-cell aggregation sensor in neuron-like cells, we demonstrate that different variants of exogenous monomeric Tau, namely full-length Tau (hTau40) and the Tau-derived construct K18 comprising the repeat domain, initially accumulate in endosomal compartments, where they form fibrillar seeds that subsequently induce the aggregation of endogenous Tau. Using superresolution imaging, we confirm that fibrils consisting of endogenous and exogenous Tau are released from cells and demonstrate their potential to spread Tau pathology. Our data indicate a greater pathological risk and potential toxicity than hitherto suspected for extracellular soluble Tau.
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- Authors
- Michel, C. H., Kumar, S., Pinotsi, D., Tunnacliffe, A., St. George-Hyslop, P., Mandelkow, E., Mandelkow, E.-M., Kaminski, C. F., & Kaminski Schierle, G. S.
- Affiliations
- University of Cambridge (GB)
- German Center for Neurodegenerative Diseases (DE)
- Center of Advanced European Studies and Research (DE)
- Corresponding author
- Kaminski, Clemens F.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 289
- Issue
- 2
- Pages
- 956-967
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3887218
- OpenAlex
- W2151048581
- Cited by
- 165
- References
- 42
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 6 · 2023: 9 · 2022: 10 · 2021: 12 · 2020: 17 · 2019: 15 · 2018: 17 · 2017: 9 · 2016: 21 · 2015: 16 · 2014: 11 · 2013: 2 · 2012: 1
- FWCI
- 12.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (089703/Z/09/Z, 100140, 089703, 081864)
- Medical Research Council (MR/K015850/1, MR/K02292X/1, MC_G1000734)
- Engineering and Physical Sciences Research Council (EP/H018301/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau aggregation, Alzheimer's disease, endosomes, tau repeat domain, super-resolution imaging
- MeSH terms
- Animals, Cell Line, Endocytosis, Exocytosis, Extracellular Space, Humans, Lysosomes, Microscopy, Electron, Models, Biological, Neurons, Endosomes, Blotting, Western, Neurofibrillary Tangles, tau Proteins, Microscopy, Confocal, Transport Vesicles, Tauopathies, Cell Line, Tumor
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