Abstract Neurons extend long axons that require maintenance and are susceptible to degeneration. Long-term integrity of axons depends on intrinsic mechanisms including axonal transport and extrinsic support from adjacent glial cells. The mechanisms of support provided by myelinating oligodendrocytes to underlying axons are only partly understood. Oligodendrocytes release extracellular vesicles (EVs) with properties of exosomes, which upon delivery to neurons improve neuronal viability in vitro . Here, we show that oligodendroglial exosome secretion is impaired in two mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wildtype oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient deprived neurons. Mutant oligodendrocytes release less exosomes that share a common signature of underrepresented proteins. Notably, mutant exosomes lack the ability to support nutrient deprived neurons and to promote axonal transport. Together, these findings indicate that glia to neuron exosome transfer promotes neuronal long-term maintenance by facilitating axonal transport, providing a novel mechanistic link between myelin diseases and secondary loss of axonal integrity.

Oligodendrocytes support axonal transport and maintenance via exosome secretion