Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair

Extracellular vesicles (EVs) carry bioactive proteins and nucleic acids that influence the behavior of target cells in multiple ways. EVs shuttle molecules between neurons and glia with apparent functional consequences on synaptic activity, morphological plasticity, and neurovascular integrity. EVs act as bidirectional vehicles in brain-periphery communication, particularly in the context of neuroinflammation and aging. Upon injury, specific types of endogenous EVs appear to play neuroprotective roles, and periphery-derived therapeutic EVs have been shown to improve neuronal regeneration. In neurodegenerative proteinopathies, EVs may play complex roles in the spreading, formation, and clearance of toxic aggregates. The physiology of the central nervous system (CNS) is built on a foundation of connection, integration, and the exchange of complex information among brain cells. Emerging evidence indicates that extracellular vesicles (EVs) are key players in the intercellular communication that underlies physiological processes such as synaptic plasticity and the maintenance of myelination. Furthermore, upon injury to the CNS, EVs may propagate inflammation across the blood–brain barrier and beyond, and also appear to mediate neuroprotection and modulate regenerative processes. In neurodegenerative diseases, EVs may play roles in the formation, spreading, and clearance of toxic protein aggregates. Here, we discuss the physiological roles of EVs in the healthy and the diseased CNS, with a focus on recent findings and emerging concepts. The physiology of the central nervous system (CNS) is built on a foundation of connection, integration, and the exchange of complex information among brain cells. Emerging evidence indicates that extracellular vesicles (EVs) are key players in the intercellular communication that underlies physiological processes such as synaptic plasticity and the maintenance of myelination. Furthermore, upon injury to the CNS, EVs may propagate inflammation across the blood–brain barrier and beyond, and also appear to mediate neuroprotection and modulate regenerative processes. In neurodegenerative diseases, EVs may play roles in the formation, spreading, and clearance of toxic protein aggregates. Here, we discuss the physiological roles of EVs in the healthy and the diseased CNS, with a focus on recent findings and emerging concepts. a rapid release of cytokines, chemokines, and other inflammatory mediators into the circulation in response to trauma or infection. In the case of brain trauma, the cytokine response leads to an increase in blood–brain barrier permeability and an increase in immune cell infiltration to the brain – among other effects. contact points or junctions between cells that are intracellularly linked to the actin cytoskeleton. transfer of material from one individual to another, for example, the transfer of circulating extracellular vesicles from a sick individual to a healthy individual, or vice versa. α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; ionotropic transmembrane receptor for the excitatory neurotransmitter glutamate. The primary mediator of excitatory neurotransmission in the mammalian brain. a highly selective, semipermeable barrier formed by vascular endothelial cells, which separates the brain’s extracellular fluid from the peripheral circulation. The BBB is important in preventing the passive diffusion of potentially dangerous substances to the brain. thin, tubular extensions from cells that can mediate cell-to-cell signaling. naturally occurring lipid-based substances that bind neuronal cannabinoid receptors and thereby modify synaptic transmission. a series of protein complexes (ESCRT0–III) collectively involved in binding and clustering ubiquitinated cargo, sorting it into endosomes, and subsequently pinching off small intraluminal vesicles to form a multivesicular endosome. an environmental modification that enables greater social and physical interactions through toys, running wheels, labyrinths, etc. and has been linked to improved neurogenesis and memory. a family of signaling proteins that bind to Eph receptors. Ephrins have a multitude of functions in the central nervous system, including acting as guidance cues for developing axons and regulating synaptic plasticity in adulthood. the genetic material encoding the core structural proteins of retroviruses, such as HIV. multipotent cells with a high capacity for self-renewal, commonly obtained from bone marrow or adipose tissue. MSCs can differentiate into a variety of cell types, including adipocytes (fat cells), chondrocytes (cartilage-producing cells), osteoblasts (bone cells), and myocytes (muscle cells). microRNA, a small noncoding RNA that acts in post-transcriptional regulation of gene expression. a kinase that assembles with specific proteins in two functionally distinct complexes (mTORC1 and mTORC2) to integrate a multitude of upstream signals, for example from growth factors, and relay the message for regulation of cell growth, metabolism, and survival. insoluble intracellular fibers of aggregated proteins, which are thought to contribute to neurotoxicity in degenerative diseases. an experimental treatment where cells are placed in low-glucose medium and their oxygen supply is restricted. Generally used as an in vitro model of stroke, where blood flow and therefore the delivery of oxygen and nutrients to the cells would be restricted. Ras homolog gene family member A. A small cytoplasmic GTPase that integrates many different cues, upstream of the ROCKs. Activation of the RhoA–ROCK pathway results, for example, in cytoskeletal rearrangements that regulate cell adhesion, shape, and process formation. Relevant in CNS regeneration as the RhoA–ROCK pathway is involved in growth cone collapse and neurite outgrowth. small swellings at presynaptic axon terminals, where neurotransmitters are stored in synaptic vesicles. structural and functional changes in synapses that impact subsequent synaptic efficacy, that is, a strengthening or a weakening of the synapse, in response to changes in the activity of the synapse. the process of elimination of synapses during brain development, or as part of learning. a family of signaling proteins that are involved in embryonic development, cell fate specification, migration, and proliferation. In the nervous system, Wnt signaling is additionally important in axon guidance, synaptogenesis, and synaptic plasticity. insoluble extracellular depositions containing aggregated Aβ peptides, which are thought to contribute to Alzheimer’s disease pathology. Aβ peptides are cleaved fragments of the amyloid precursor protein.