TY  - JOUR
AU  - Wang, Yipeng
AU  - Balaji, Varun
AU  - Kaniyappan, Senthilvelrajan
AU  - Krüger, Lars
AU  - Irsen, Stephan
AU  - Tepper, Katharina
AU  - Chandupatla, Ram Reddy
AU  - Maetzler, Walter
AU  - Schneider, Anja
AU  - Mandelkow, Eckhard
AU  - Mandelkow, Eva-Maria
TI  - The release and trans-synaptic transmission of Tau via exosomes.
JO  - Molecular neurodegeneration
VL  - 12
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2020-05427
SP  - 5
PY  - 2017
AB  - 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.
KW  - Adult
KW  - Aged
KW  - Aged, 80 and over
KW  - Alzheimer Disease: pathology
KW  - Animals
KW  - Cryoelectron Microscopy
KW  - Disease Progression
KW  - Enzyme-Linked Immunosorbent Assay
KW  - Exosomes: metabolism
KW  - Female
KW  - Flow Cytometry
KW  - Fluorescent Antibody Technique
KW  - Humans
KW  - Male
KW  - Mice
KW  - Microfluidic Analytical Techniques
KW  - Microscopy, Atomic Force
KW  - Middle Aged
KW  - Neurons: metabolism
KW  - Protein Transport
KW  - Rats
KW  - Tauopathies: metabolism
KW  - Tauopathies: pathology
KW  - tau Proteins: metabolism
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28086931
C2  - pmc:PMC5237256
DO  - DOI:10.1186/s13024-016-0143-y
UR  - https://pub.dzne.de/record/139105
ER  -