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@ARTICLE{Wang:139105,
      author       = {Wang, Yipeng and Balaji, Varun and Kaniyappan,
                      Senthilvelrajan and Krüger, Lars and Irsen, Stephan and
                      Tepper, Katharina and Chandupatla, Ram Reddy and Maetzler,
                      Walter and Schneider, Anja and Mandelkow, Eckhard and
                      Mandelkow, Eva-Maria},
      title        = {{T}he release and trans-synaptic transmission of {T}au via
                      exosomes.},
      journal      = {Molecular neurodegeneration},
      volume       = {12},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2020-05427},
      pages        = {5},
      year         = {2017},
      abstract     = {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.},
      keywords     = {Adult / Aged / Aged, 80 and over / Alzheimer Disease:
                      pathology / Animals / Cryoelectron Microscopy / Disease
                      Progression / Enzyme-Linked Immunosorbent Assay / Exosomes:
                      metabolism / Female / Flow Cytometry / Fluorescent Antibody
                      Technique / Humans / Male / Mice / Microfluidic Analytical
                      Techniques / Microscopy, Atomic Force / Middle Aged /
                      Neurons: metabolism / Protein Transport / Rats /
                      Tauopathies: metabolism / Tauopathies: pathology / tau
                      Proteins: metabolism / tau Proteins (NLM Chemicals)},
      cin          = {AG Mandelkow 1 / AG Mandelkow 2 / Tech Transfer / Clinical
                      Dementia Research Bonn},
      ddc          = {570},
      cid          = {I:(DE-2719)1013014 / I:(DE-2719)1013015 /
                      I:(DE-2719)1030028 / I:(DE-2719)1011305},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28086931},
      pmc          = {pmc:PMC5237256},
      doi          = {10.1186/s13024-016-0143-y},
      url          = {https://pub.dzne.de/record/139105},
}