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Mechanisms of axonal support by oligodendrocyte-derived extracellular vesicles

Nature Reviews Neuroscience volume 24, pages 474–486 (2023)Cite this article

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Abstract

Extracellular vesicles (EVs) have recently emerged as versatile elements of cell communication in the nervous system, mediating tissue homeostasis. EVs influence the physiology of their target cells via horizontal transfer of molecular cargo between cells and by triggering signalling pathways. In this Review, we discuss recent work revealing that EVs mediate interactions between oligodendrocytes and neurons, which are relevant for maintaining the structural integrity of axons. In response to neuronal activity, myelinating oligodendrocytes release EVs, which are internalized by neurons and provide axons with key factors that improve axonal transport, stress resistance and energy homeostasis. Glia-to-neuron transfer of EVs is thus a crucial facet of axonal preservation. When glial support is impaired, axonal integrity is progressively lost, as observed in myelin-related disorders, other neurodegenerative diseases and with normal ageing. We highlight the mechanisms that oligodendroglial EVs use to sustain axonal integrity and function.

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Fig. 1: Axon–glia interactions and proposed axon-supporting functions of oligodendrocytes.
Fig. 2: Exosomes in oligodendrocyte–axon communication.
Fig. 3: Functions of exosomes in axonal maintenance and integrity.
Fig. 4: Mechanisms of glial support: cooperation between exosome-dependent and metabolic support.

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Acknowledgements

The authors dedicate this article to the memory of Marie T. Filbin and Steven E. Pfeiffer in appreciation of their pioneering work on the cell biology of oligodendrocytes. The authors thank J. Trotter and K.-A. Nave for discussions. E.-M.K.-A. is supported by the Deutsche Forschungsgemeinschaft (grants KR 3668/1-2 and KR 3668/2-2). H.B.W. is supported by the Deutsche Forschungsgemeinschaft (grants WE 2720/2-2, WE 2720/4-1 and WE 2720/5-1).

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  1. Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany

    Eva-Maria Krämer-Albers

  2. Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany

    Hauke B. Werner

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  1. Eva-Maria Krämer-Albers
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Both authors contributed equally to the preparation of this manuscript.

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Correspondence to Eva-Maria Krämer-Albers.

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Glossary

2′,3′-Cyclic nucleotide 3′-phosphodiesterase

(CNP). The third-most abundant protein of CNS myelin.

Endosomal sorting complex required for transport

A multicomponent protein complex facilitating various steps of membrane remodelling.

Exosomal escape

A mechanism by which exosomal cargo fuses with and integrates into the target cell and acquires biological activity.

Exosomes

A subclass of extracellular vesicles released by fusion of multivesicular endosomes with the plasma membrane and are the endosomal intraluminal vesicles that are formed by inward budding of the limiting membrane.

Extracellular vesicles

(EVs). Umbrella term for different types of vesicle released by cells comprising cytoplasmic content and membrane surface-expressed epitopes.

Fluorescence resonance energy transfer-sensor imaging

Biosensors that allow visualization of dynamic molecular events in living cells, including the generation of ATP from ADP or changes in cytosolic calcium levels.

Hereditary spastic paraplegia

(SPG). A heterogenous group of progressive gait disorders caused by dysfunction or degeneration of long-projecting axons in the spinal cord.

Hypomyelinating leukodystrophy

(HLD). Umbrella term for a heterogenous group of severe neurodegenerative disorders primarily affecting white matter physiology.

Multivesicular endosomes

Spherical organelles of the late endosomal system that are packed with internal vesicles and can either fuse with lysosomes to degrade the internal material or fuse with the plasma membrane to release their content into the extracellular space.

Non-compacted cytoplasmic myelin subcompartment

Cytosolic sub-compartments of myelin including the adaxonal myelin layer, paranodal myelin and myelinic channels through otherwise compact myelin.

Periaxonal space

Extracellular space between the plasma membrane of an axon and the adjacent adaxonal myelin membrane.

Proteolipid protein

(PLP). A cholesterol-associated, tetraspan-transmembrane protein; the most abundant protein of CNS myelin.

Reducing equivalent

Chemical species that transfer electrons in a redox reaction.

Sirtuin-2

(SIRT2). An NAD+-dependent deacetylase that is highly expressed in oligodendrocytes.

Sphingomyelinase

An enzyme that cleaves the phosphodiester bond of sphingomyelin generating ceramide and phosphocholine.

Tetraspanins

A protein family containing four transmembrane domains and two extracellular domains that organize proteins and lipids in membrane subdomains (tetraspanin-enriched microdomains).

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Krämer-Albers, EM., Werner, H.B. Mechanisms of axonal support by oligodendrocyte-derived extracellular vesicles. Nat. Rev. Neurosci. 24, 474–486 (2023). https://doi.org/10.1038/s41583-023-00711-y

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