Journal Article

DZNE-2020-05427

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The release and trans-synaptic transmission of Tau via exosomes.

Wang, Y. (First author)DZNE* ; Balaji, V.DZNE* ; Kaniyappan, S.DZNE* ; Krüger, L.DZNE* ; Irsen, S. ; Tepper, K.DZNE* ; Chandupatla, R. R.DZNE* ; Maetzler, W. ; Schneider, A.DZNE* ; Mandelkow, E.DZNE* ; Mandelkow, E.-M. (Last author)DZNE*

2017
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s13024-016-0143-y

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.

Keyword(s): Adult (MeSH) ; Aged (MeSH) ; Aged, 80 and over (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Animals (MeSH) ; Cryoelectron Microscopy (MeSH) ; Disease Progression (MeSH) ; Enzyme-Linked Immunosorbent Assay (MeSH) ; Exosomes: metabolism (MeSH) ; Female (MeSH) ; Flow Cytometry (MeSH) ; Fluorescent Antibody Technique (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Microfluidic Analytical Techniques (MeSH) ; Microscopy, Atomic Force (MeSH) ; Middle Aged (MeSH) ; Neurons: metabolism (MeSH) ; Protein Transport (MeSH) ; Rats (MeSH) ; Tauopathies: metabolism (MeSH) ; Tauopathies: pathology (MeSH) ; tau Proteins: metabolism (MeSH) ; tau Proteins

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Contributing Institute(s):

1. Structural Principles of Neurodegeneration (AG Mandelkow 1)
2. Cell and Animal Models of Neurodegeneration (AG Mandelkow 2)
3. Technology Transfer and Industry Collaborations Unit (Tech Transfer)
4. Clinical Dementia Research Bonn (Clinical Dementia Research Bonn)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2017

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection

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