001     139105
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024 7 _ |a 10.1186/s13024-016-0143-y
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024 7 _ |a pmc:PMC5237256
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037 _ _ |a DZNE-2020-05427
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Wang, Yipeng
|0 P:(DE-2719)2810339
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245 _ _ |a The release and trans-synaptic transmission of Tau via exosomes.
260 _ _ |a London
|c 2017
|b Biomed Central
264 _ 1 |3 online
|2 Crossref
|b Springer Science and Business Media LLC
|c 2017-01-13
264 _ 1 |3 print
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|b Springer Science and Business Media LLC
|c 2017-12-01
336 7 _ |a article
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520 _ _ |a Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages ('Braak stages'). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes.Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau.We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells.Our study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies.
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650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Aged, 80 and over
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Cryoelectron Microscopy
|2 MeSH
650 _ 2 |a Disease Progression
|2 MeSH
650 _ 2 |a Enzyme-Linked Immunosorbent Assay
|2 MeSH
650 _ 2 |a Exosomes: metabolism
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Flow Cytometry
|2 MeSH
650 _ 2 |a Fluorescent Antibody Technique
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Microfluidic Analytical Techniques
|2 MeSH
650 _ 2 |a Microscopy, Atomic Force
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Protein Transport
|2 MeSH
650 _ 2 |a Rats
|2 MeSH
650 _ 2 |a Tauopathies: metabolism
|2 MeSH
650 _ 2 |a Tauopathies: pathology
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
700 1 _ |a Balaji, Varun
|0 P:(DE-2719)2812372
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700 1 _ |a Kaniyappan, Senthilvelrajan
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700 1 _ |a Krüger, Lars
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700 1 _ |a Irsen, Stephan
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700 1 _ |a Tepper, Katharina
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700 1 _ |a Chandupatla, Ram Reddy
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700 1 _ |a Maetzler, Walter
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700 1 _ |a Schneider, Anja
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700 1 _ |a Mandelkow, Eckhard
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700 1 _ |a Mandelkow, Eva-Maria
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773 1 8 |a 10.1186/s13024-016-0143-y
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|t Molecular Neurodegeneration
|v 12
|y 2017
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773 _ _ |a 10.1186/s13024-016-0143-y
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|t Molecular neurodegeneration
|v 12
|y 2017
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856 4 _ |y OpenAccess
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LibraryCollectionCLSMajorCLSMinorLanguageAuthor
Marc 21