Fate and propagation of endogenously formed Tau aggregates in neuronal cells
Abstract Tau accumulation in the form of neurofibrillary tangles in the brain is a hallmark of tauopathies such as Alzheimer's disease (AD). Tau aggregates accumulate in brain regions in a defined spatiotemporal pattern and may induce the aggregation of native Tau in a prion‐like manner. Howeve...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012025 |
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| _version_ | 1849332135016529920 |
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| author | Patricia Chastagner Frida Loria Jessica Y Vargas Josh Tois Marc I Diamond George Okafo Christel Brou Chiara Zurzolo |
| author_facet | Patricia Chastagner Frida Loria Jessica Y Vargas Josh Tois Marc I Diamond George Okafo Christel Brou Chiara Zurzolo |
| author_sort | Patricia Chastagner |
| collection | DOAJ |
| description | Abstract Tau accumulation in the form of neurofibrillary tangles in the brain is a hallmark of tauopathies such as Alzheimer's disease (AD). Tau aggregates accumulate in brain regions in a defined spatiotemporal pattern and may induce the aggregation of native Tau in a prion‐like manner. However, the underlying mechanisms of cell‐to‐cell spreading of Tau pathology are unknown and could involve encapsulation within exosomes, trans‐synaptic passage, and tunneling nanotubes (TNTs). We have established a neuronal cell model to monitor both internalization of externally added fibrils, synthetic (K18) or Tau from AD brain extracts, and real‐time conversion of microtubule‐binding domain of Tau fused to a fluorescent marker into aggregates. We found that these endogenously formed deposits colabel with ubiquitin and p62 but are not recruited to macroautophagosomes, eventually escaping clearance. Furthermore, endogenous K18‐seeded Tau aggregates spread to neighboring cells where they seed new deposits. Transfer of Tau aggregates depends on direct cell contact, and they are found inside TNTs connecting neuronal cells. We further demonstrate that contact‐dependent transfer occurs in primary neurons and between neurons and astrocytes in organotypic cultures. |
| format | Article |
| id | doaj-art-ac1f9fb33cb0485ebf048cfa49feb9f0 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-ac1f9fb33cb0485ebf048cfa49feb9f02025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-11-01121212010.15252/emmm.202012025Fate and propagation of endogenously formed Tau aggregates in neuronal cellsPatricia Chastagner0Frida Loria1Jessica Y Vargas2Josh Tois3Marc I Diamond4George Okafo5Christel Brou6Chiara Zurzolo7Unité de Trafic Membranaire et Pathogenèse, Institut PasteurUnité de Trafic Membranaire et Pathogenèse, Institut PasteurUnité de Trafic Membranaire et Pathogenèse, Institut PasteurUnité de Trafic Membranaire et Pathogenèse, Institut PasteurCenter for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical CenterGlaxoSmithKlineUnité de Trafic Membranaire et Pathogenèse, Institut PasteurUnité de Trafic Membranaire et Pathogenèse, Institut PasteurAbstract Tau accumulation in the form of neurofibrillary tangles in the brain is a hallmark of tauopathies such as Alzheimer's disease (AD). Tau aggregates accumulate in brain regions in a defined spatiotemporal pattern and may induce the aggregation of native Tau in a prion‐like manner. However, the underlying mechanisms of cell‐to‐cell spreading of Tau pathology are unknown and could involve encapsulation within exosomes, trans‐synaptic passage, and tunneling nanotubes (TNTs). We have established a neuronal cell model to monitor both internalization of externally added fibrils, synthetic (K18) or Tau from AD brain extracts, and real‐time conversion of microtubule‐binding domain of Tau fused to a fluorescent marker into aggregates. We found that these endogenously formed deposits colabel with ubiquitin and p62 but are not recruited to macroautophagosomes, eventually escaping clearance. Furthermore, endogenous K18‐seeded Tau aggregates spread to neighboring cells where they seed new deposits. Transfer of Tau aggregates depends on direct cell contact, and they are found inside TNTs connecting neuronal cells. We further demonstrate that contact‐dependent transfer occurs in primary neurons and between neurons and astrocytes in organotypic cultures.https://doi.org/10.15252/emmm.202012025autophagyIntercellular spreadingprion‐like seedingTau aggregatestunneling nanotubes |
| spellingShingle | Patricia Chastagner Frida Loria Jessica Y Vargas Josh Tois Marc I Diamond George Okafo Christel Brou Chiara Zurzolo Fate and propagation of endogenously formed Tau aggregates in neuronal cells EMBO Molecular Medicine autophagy Intercellular spreading prion‐like seeding Tau aggregates tunneling nanotubes |
| title | Fate and propagation of endogenously formed Tau aggregates in neuronal cells |
| title_full | Fate and propagation of endogenously formed Tau aggregates in neuronal cells |
| title_fullStr | Fate and propagation of endogenously formed Tau aggregates in neuronal cells |
| title_full_unstemmed | Fate and propagation of endogenously formed Tau aggregates in neuronal cells |
| title_short | Fate and propagation of endogenously formed Tau aggregates in neuronal cells |
| title_sort | fate and propagation of endogenously formed tau aggregates in neuronal cells |
| topic | autophagy Intercellular spreading prion‐like seeding Tau aggregates tunneling nanotubes |
| url | https://doi.org/10.15252/emmm.202012025 |
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