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 2 mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wild-type oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient-deprived neurons. Mutant oligodendrocytes release fewer exosomes, which 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.

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 exosomes support neurons by promoting fast axonal transport, most strikingly under conditions of oxidative stress and nutrient deprivation. Interestingly, oligodendroglial exosome secretion is impaired in two mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. 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.Here, we studied the effect of oligodendroglial sEVs on axonal maintenance and examined their impact on fast axonal transport by live-cell imaging of vesicular cargo travelling along axons. We show that adding sEVs to neurons promotes axonal transport most prominently under conditions of cell stress. Intriguingly, we found that the release of sEVs from PLP-and CNP-deficient oligodendrocytes is impaired and that mutant sEVs, which share a common altered proteome signature, are dysfunctional. We conclude that sEVs of exosomal nature delivered from oligodendrocytes to neurons contribute to axonal homeostasis and long-term maintenance by facilitating axonal transport. Secondary axonal degeneration, as observed in PLP-and CNP-deficient mice, is coupled to glial exosome function providing a so far missing link between glial dysfunction, axonal transport and axonal degeneration as seen in various neurological diseases.

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Opto;genetic stimulation of a hippocampal engram activates fear memory recall.