title: The release and trans-synaptic transmission of Tau via exosomes.
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.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. Yipeng.wang@dzne.de.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Varun
authors.initials: V
authors.lastname: Balaji
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Senthilvelrajan
authors.initials: S
authors.lastname: Kaniyappan
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Krüger
authors.affiliation: CAESAR Research Center, Bonn, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Irsen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Tepper
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: RamReddy
authors.initials: R
authors.lastname: Chandupatla
authors.affiliation: Department of Neurology, University of Tübingen, Tübingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department for Psychiatry and Psychotherapy, University Medical Center, Goettingen, Germany.|MPI for Experimental Medicine, Göttingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schneider
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|CAESAR Research Center, Bonn, Germany.|MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Hamburg, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. mandelkow@mpasmb.desy.de.|CAESAR Research Center, Bonn, Germany. mandelkow@mpasmb.desy.de.|MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Hamburg, Germany. mandelkow@mpasmb.desy.de.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D020285:Cryoelectron Microscopy; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D051379:Mice; D046210:Microfluidic Analytical Techniques; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: Alzheimer disease; Exosomes; Spreading; Tau