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000139105 041__ $$aEnglish
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000139105 1001_ $$0P:(DE-2719)2810339$$aWang, Yipeng$$b0$$eFirst author$$udzne
000139105 245__ $$aThe release and trans-synaptic transmission of Tau via exosomes.
000139105 260__ $$aLondon$$bBiomed Central$$c2017
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000139105 520__ $$aTau 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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000139105 650_7 $$2NLM Chemicals$$atau Proteins
000139105 650_2 $$2MeSH$$aAdult
000139105 650_2 $$2MeSH$$aAged
000139105 650_2 $$2MeSH$$aAged, 80 and over
000139105 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000139105 650_2 $$2MeSH$$aAnimals
000139105 650_2 $$2MeSH$$aCryoelectron Microscopy
000139105 650_2 $$2MeSH$$aDisease Progression
000139105 650_2 $$2MeSH$$aEnzyme-Linked Immunosorbent Assay
000139105 650_2 $$2MeSH$$aExosomes: metabolism
000139105 650_2 $$2MeSH$$aFemale
000139105 650_2 $$2MeSH$$aFlow Cytometry
000139105 650_2 $$2MeSH$$aFluorescent Antibody Technique
000139105 650_2 $$2MeSH$$aHumans
000139105 650_2 $$2MeSH$$aMale
000139105 650_2 $$2MeSH$$aMice
000139105 650_2 $$2MeSH$$aMicrofluidic Analytical Techniques
000139105 650_2 $$2MeSH$$aMicroscopy, Atomic Force
000139105 650_2 $$2MeSH$$aMiddle Aged
000139105 650_2 $$2MeSH$$aNeurons: metabolism
000139105 650_2 $$2MeSH$$aProtein Transport
000139105 650_2 $$2MeSH$$aRats
000139105 650_2 $$2MeSH$$aTauopathies: metabolism
000139105 650_2 $$2MeSH$$aTauopathies: pathology
000139105 650_2 $$2MeSH$$atau Proteins: metabolism
000139105 7001_ $$0P:(DE-2719)2812372$$aBalaji, Varun$$b1$$udzne
000139105 7001_ $$0P:(DE-2719)2812350$$aKaniyappan, Senthilvelrajan$$b2$$udzne
000139105 7001_ $$0P:(DE-2719)2810335$$aKrüger, Lars$$b3$$udzne
000139105 7001_ $$0P:(DE-HGF)0$$aIrsen, Stephan$$b4
000139105 7001_ $$0P:(DE-2719)2810336$$aTepper, Katharina$$b5$$udzne
000139105 7001_ $$0P:(DE-2719)2811626$$aChandupatla, Ram Reddy$$b6$$udzne
000139105 7001_ $$0P:(DE-HGF)0$$aMaetzler, Walter$$b7
000139105 7001_ $$0P:(DE-2719)2812035$$aSchneider, Anja$$b8$$udzne
000139105 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b9$$udzne
000139105 7001_ $$0P:(DE-2719)2541658$$aMandelkow, Eva-Maria$$b10$$eLast author$$udzne
000139105 77318 $$2Crossref$$3journal-article$$a10.1186/s13024-016-0143-y$$b : Springer Science and Business Media LLC, 2017-01-13$$n1$$p5$$tMolecular Neurodegeneration$$v12$$x1750-1326$$y2017
000139105 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-016-0143-y$$gVol. 12, no. 1, p. 5$$n1$$p5$$q12:1<5$$tMolecular neurodegeneration$$v12$$x1750-1326$$y2017
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000139105 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237256
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