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Extracellular vesicles and intercellular communication within the nervous system
Valentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A. Maguire, Xandra O. Breakefield
Valentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A. Maguire, Xandra O. Breakefield
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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 1

EV-mediated intercellular communication between cells in the nervous system.

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EV-mediated intercellular communication between cells in the nervous sys...
(i) Astrocyte-derived EVs stimulate dendritic arborization of neurons by transport and release of synapsin I (21); (ii) EVs from microglia increase neuronal synaptic activity, and (iii) neuron-derived EVs activate glial cell functions, such as microglia phagocytosis for clearance of inactive synapses and toxic proteins (44, 148). (iv) EVs from oligodendrocytes enhance stress tolerance of neurons, stimulate anterograde transport of signaling molecules in neurons, and carry proteolipoprotein (PLP), which is important for myelination (9, 45). (v) Immature neural progenitor cells release proteins, such as the L1 adhesion molecule, the glycosylphosphatidyl-inositol–anchored (GPI-anchored) prion protein, and the GluR2/3 subunit of the glutamate receptor, via EVs, which participate in early brain development (7). (vi) Retrotransposons can be transported between cells through the EV compartment. During neurogenesis, the activity of retrotransposons is increased, resulting in a high degree of somatic mosaicism in neuronal genomes (31).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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