Exosome Circuitry During (De)(Re)Myelination of the Central Nervous System

Abstract

Reciprocal neuron-glia cell communication is fundamental for the proper function of the nervous system. Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that insulate and provide trophic support to neurons. This effective interaction is crucial not only for myelination but also for long-term axonal survival and neural connectivity. In recent years, exosomes have been portrayed as key players in intercellular interaction in the context of the healthy and diseased CNS. They act as communicating vehicles, true attachés operating between neurons and glial cells. Despite the complex exosome circuitry within the nervous system, experimental evidence supports the role of exosomes in modulating myelination. Oligodendrocytes secrete exosomes in response to neuronal signals in an electric activity-dependent manner. These released exosomes are then internalized by neurons, contributing to their integrity and activity. In turn, neurons secrete exosomes to control the communication between them and with myelinating cells in order to regulate synaptic function in neuronal development, myelin maintenance, and neuroregeneration. In this review, we provide a critical view of the current understanding on how exosomes, either from CNSresident cells or from the periphery, contribute to the formation and maintenance of myelin and, additionally, on how the differential content of exosomes in normal and pathological conditions foresees the use of these nanovesicles as putative diagnostic and/or therapeutical agents in white matter degeneration-associated diseases.

Function of exosomes in neurological disorders and brain tumors

“…Recent studies have found that exosomal contents such as myelin oligodendrocyte glycoprotein [ 155 ] , sphingomyelinase (SMase) [ 156 ] , and a variety of microRNA [ 157 – 160 ] are potential diagnostic biomarkers for MS. In addition, Schwann cell-derived exosomes contain a variety of neuroprotective proteins and anti-inflammatory factors [ 161 ] that play critical roles in MS via regulating myelin membrane biogenesis and providing trophic factors required for myelin maintenance [ 162 ] . For instance, exosomes which contain myelin and protective proteins against stress, were released from oligodendrocytes into the extracellular space in a calcium dependent manner [ 163 ] ; Schwann cell-derived exosomes can improve axonal regeneration after axotomy [ 164 ] , and increase nerve activity [ 165 ] .…”

Exosomes: Potential Disease Biomarkers and New Therapeutic Targets

“…Brain exosomes also play an important role in central nervous system (CNS) homeostasis and can contribute to the communication between cells whether they are neighboring or distant [6]. Oligodendrocyte-derived exosomes contain myelin proteins and lipids, including Folch-Lees proteolipid, CNPase, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, cholesterol, and sphingolipids, as well as other molecules, such as heat shock proteins, which act directly on other oligodendrocytes, neurons or microglia to regulate myelin biogenesis, degradation and maintenance, as well as to provide neuronal trophic support [88]. Additionally, oligodendroglial exosomes exert beneficial effects on neurons, potentially through the transfer of protective proteins, such as catalase and superoxide dismutase.…”

The Role of Extracellular Vesicles in Demyelination of the Central Nervous System

“…Moreover, in response to neuronal signals, OLs secrete exosomes in an electric activity-dependent manner which are internalized by neurons, affecting their activity. Conversely, neurons can also secrete exosomes that may influence myelin maintenance and regeneration [41]. In addition, OLs stimulated with glutamate secrete exosomes which, when internalized by neurons, have been shown to exert several positive effects, such as resistance to oxidative stress (via transfer of superoxide dismutase and catalase), enhancement of neuronal survival during oxygen-glucose deprivation and increased neuronal firing rate [43,77].…”

“…In addition, OLs stimulated with glutamate secrete exosomes which, when internalized by neurons, have been shown to exert several positive effects, such as resistance to oxidative stress (via transfer of superoxide dismutase and catalase), enhancement of neuronal survival during oxygen-glucose deprivation and increased neuronal firing rate [43,77]. Therefore, exosomes secreted by OLs after neuronal signals may transport components for myelin membrane biogenesis and, moreover, they may transfer trophic and survival factors to nearby axons under homeostatic and stress conditions, in order to support myelination and myelin maintenance [41].…”

“…The multifaceted functions of EVs in the nervous system are increasingly being studied [35][36][37][38], revealing that EVs are crucial mediators of processes such as inflammation [39,40], myelination [41,42] and neuron-glia communication [43,44]. In addition, several studies have reported the participation of EVs in myelination and demyelination [45].…”