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Extracellular vesicles and intercellular communication within the nervous system
Valentina Zappulli, … , Casey A. Maguire, Xandra O. Breakefield
Valentina Zappulli, … , Casey A. Maguire, Xandra O. Breakefield
Published April 1, 2016
Citation Information: J Clin Invest. 2016;126(4):1198-1207. https://doi.org/10.1172/JCI81134.
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Review Series

Extracellular vesicles and intercellular communication within the nervous system

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Abstract

Extracellular vesicles (EVs, including exosomes) are implicated in many aspects of nervous system development and function, including regulation of synaptic communication, synaptic strength, and nerve regeneration. They mediate the transfer of packets of information in the form of nonsecreted proteins and DNA/RNA protected within a membrane compartment. EVs are essential for the packaging and transport of many cell-fate proteins during development as well as many neurotoxic misfolded proteins during pathogenesis. This form of communication provides another dimension of cellular crosstalk, with the ability to assemble a “kit” of directional instructions made up of different molecular entities and address it to specific recipient cells. This multidimensional form of communication has special significance in the nervous system. How EVs help to orchestrate the wiring of the brain while allowing for plasticity associated with learning and memory and contribute to regeneration and degeneration are all under investigation. Because they carry specific disease-related RNAs and proteins, practical applications of EVs include potential uses as biomarkers and therapeutics. This Review describes our current understanding of EVs and serves as a springboard for future advances, which may reveal new important mechanisms by which EVs in coordinate brain and body function and dysfunction.

Authors

Valentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A. Maguire, Xandra O. Breakefield

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Figure 2

EVs in nervous system physiology and pathology.

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EVs in nervous system physiology and pathology.
(A) The role of EVs in s...
(A) The role of EVs in synaptic communication. The addition of GABAA receptor antagonists results in the release of presynaptic EVs that are taken up by postsynaptic cells and modulate synaptic strength and retrograde signaling. They can also activate glial functions, such as microglia phagocytosis for clearance of inactive synapses and release of cytokines and complement. Synaptic vesicles (SV) fuse with the plasma membrane to release neurotransmitters (NT) into the extracellular space, which bind to receptors on postsynaptic neurons, while EVs are released intact into this space by fusion of multivesicular bodies (MVB) with the plasma membrane or budding from the plasma membrane. (B) The role of EVs in axonal regeneration in the peripheral nervous system is mediated by Schwann cells that release EVs containing proteins, miRNA, mRNA, and ribosomes to promote axonal growth. (C) In the pathogenesis of neurodegenerative diseases, (i) EVs can modulate phagocytic clearing of misfolded proteins, such as that described for Aβ in AD. On the other hand, EVs can promote extracellular release, (ii) cell-to-cell spreading, and (iii) accumulation of toxic proteins such as tau, SOD1, TDP-43, and prions, all of which are associated with neuronal degeneration.

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