Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology
| Autor: | 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. |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
metabolism [Endosomes]
Amyloid Blotting Western tau Proteins Endosomes Models Biological Exocytosis Cell Line metabolism [Lysosomes] Neurobiology Alzheimer Disease Cell Line Tumor mental disorders metabolism [Extracellular Space] pathology [Neurons] Animals Humans Transport Vesicles Propagation Neurons Fluorescence Lifetime Imaging Microscopy Microscopy Confocal Neurofibrillary Tangles Protein Aggregation metabolism [tau Proteins] Endocytosis Microscopy Electron metabolism [Neurofibrillary Tangles] Tauopathies metabolism [Neurons] ddc:540 metabolism [Transport Vesicles] Superresolution Microscopy ultrastructure [Neurofibrillary Tangles] metabolism [Tauopathies] Tau Extracellular Space Lysosomes |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry The journal of biological chemistry 289(2), 956-967 (2013). doi:10.1074/jbc.M113.515445 |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M113.515445 |
| Popis: | Background: The aggregation and stereotypic spreading of Tau protein is associated with Alzheimer disease. Results: Monomeric Tau enters neurons and nucleates and engages endogenous Tau to aggregate. Conclusion: Endocytosis of soluble Tau triggers aggregation in vesicles and is sufficient to initiate the spreading of pathological species. Significance: Increased levels of extracellular monomeric Tau may increase the risk of developing tauopathies. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|