Extracellular Vesicles Secreted by Astroglial Cells Transport Apolipoprotein D to Neurons and Mediate Neuronal Survival Upon Oxidative Stress

Abstract

Extracellular vesicle (EV)-mediated glia-to-neuron communication has been recognized in a growing number of physiological and pathological situations. They transport complex sets of molecules that can be beneficial or detrimental for the receiving cell. As in other areas of biology, their analysis is revolutionizing the field of neuroscience, since fundamental signaling processes are being re-evaluated, and applications for neurodegenerative disease therapies have emerged. Using human astrocytic and differentiated neuronal cell lines, we demonstrate that a classical neuroprotective protein, Apolipoprotein D (ApoD), expressed by glial cells and known to promote functional integrity and survival of neurons, is exclusively transported by EVs from astrocytes to neurons, where it gets internalized. Indeed, we demonstrate that conditioned media derived from ApoD-knock-out (KO) astrocytes exert only a partial autocrine protection from oxidative stress (OS) challenges, and that EVs are required for ApoD-positive astrocytic cell line derived medium to exert full neuroprotection. When subfractionation of EVs is performed, ApoD is revealed as a very specific marker of the exosome-containing fractions. These discoveries help us reframe our understanding of the neuroprotective role of this lipid binding protein and open up new research avenues to explore the use of systemically administered ApoD-loaded exosomes that can cross the blood-brain barrier to treat neurodegenerative diseases.

Role of Exosomes in Cancer-Related Cognitive Impairment

“…Exosomes with neuroprotective properties have been described as taking part in an important mechanism contributing to neuronal survival and function. A recent study revealed that astroglial released exosomes containing Apolipoprotein D (ApoD) have neuroprotective roles in neurons [57]. The investigators reported that the uptake of ApoD-exosomes by neuronal cells showed greater viability under oxidative stress, suggesting that ApoD-exosomes might promote functional integrity as well as the survival of neurons [57].…”

“…A recent study revealed that astroglial released exosomes containing Apolipoprotein D (ApoD) have neuroprotective roles in neurons [57]. The investigators reported that the uptake of ApoD-exosomes by neuronal cells showed greater viability under oxidative stress, suggesting that ApoD-exosomes might promote functional integrity as well as the survival of neurons [57]. Xin et al reported that miR-17-92 cluster-enriched exosomes could activate the PI3K/Akt/mTOR/GSK-3β signaling pathway and enhance neural plasticity and functional recovery in rodents with stroke [58].…”

Influence of species and processing parameters on recovery and content of brain tissue-derived extracellular vesicles

“…Additionally, sensitive proteomics methods indicated several cellular or coisolate markers, including calnexin, GLIPR2, and ApoD in sEVs, though we did not find Calnexin or GM130 expression by WB. These proteins that are associated with intracellular compartments beyond plasma membrane (PM)/ endosomes 54 may be contaminants, but could also be bona fide cargo of small bdEVs [55][56][57][58][59] : calnexin is carried by syncytiotrophoblast EVs with immunoregulatory function in preeclampsia 56 , while ApoD transported by astroglial cells can exert neuroprotective effects 58 . Numerous cytosolic, annexin, Rab, and cytoskeleton proteins were also found.…”

Brain-Derived Extracellular Vesicles are Highly Enriched in the Prion Protein and Its C1 Fragment: Relevance for Cellular Uptake and Implications in Stroke

“…Since there is close communication between astrocytes and microglia after injury, and given that activated astrocytes can in turn contribute to the activation of distant microglia after ischemia 78 , it may be that the release of EVs from astrocytes at 24h is a factor facilitating the spread of reactive microglia. Moreover, astrocytes present neuroprotective features after stroke 79 and neurons exposed to reactive oxygen species (ROS) showed increased survival when treated with astrocytic EVs 80 . Whether the relative increase in astrocytic sEVs is related to microglia proliferation, the formation of the glial scar, or for protection against ROS, clearly deserves further studies.…”