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Filannino, F.M.; Panaro, M.A.; Benameur, T.; Pizzolorusso, I.; Porro, C. Extracellular Vesicles in the Central Nervous System. Encyclopedia. Available online: https://encyclopedia.pub/entry/54480 (accessed on 14 June 2024).
Filannino FM, Panaro MA, Benameur T, Pizzolorusso I, Porro C. Extracellular Vesicles in the Central Nervous System. Encyclopedia. Available at: https://encyclopedia.pub/entry/54480. Accessed June 14, 2024.
Filannino, Francesca Martina, Maria Antonietta Panaro, Tarek Benameur, Ilaria Pizzolorusso, Chiara Porro. "Extracellular Vesicles in the Central Nervous System" Encyclopedia, https://encyclopedia.pub/entry/54480 (accessed June 14, 2024).
Filannino, F.M., Panaro, M.A., Benameur, T., Pizzolorusso, I., & Porro, C. (2024, January 29). Extracellular Vesicles in the Central Nervous System. In Encyclopedia. https://encyclopedia.pub/entry/54480
Filannino, Francesca Martina, et al. "Extracellular Vesicles in the Central Nervous System." Encyclopedia. Web. 29 January, 2024.
Extracellular Vesicles in the Central Nervous System
Edit
Communication in the central nervous system (CNS) is fundamental for different biological functions including brain development, homeostasis preservation, and neural circuit formation. Indeed, the crosstalk between glia and neurons is critical in the CNS for a variety of biological functions, such as brain development, neural circuit maturation, and homeostasis maintenance. Glia cells are involved in different processes including inflammatory responses to infections or diseases, neurotrophic support, and synaptic remodelling and pruning. In addition to the traditional direct cell-to-cell contact, glial cell can also communicate with neurons through the paracrine action of secreted molecules, or by the release and reception of extracellular vesicles (EVs). EVs, which are subdivided into three subtypes: microvesicles, exosomes, and apoptotic bodies, are a major constituent of the cell secretome. EVs have the ability to circulate in the extracellular body fluid and modulate several biological processes and their associated pathways. EVs cross the blood–brain barrier (BBB) bidirectionally from the bloodstream to the brain parenchyma and vice versa. They play an important role in brain–periphery communication in physiology and pathophysiology. According to the current literature, although EVs cross the BBB, it is unclear how, where, and when they can overcome this tightly controlled cellular barrier.
extracellular vesicle microglia astrocytes oligodendrocytes communication central nervous system cells

1.  Extracellular Vesicles in the Central Nervous System

Brain-derived vesicles are a heterogeneous population of central nervous system (CNS)-derived extracellular vesicles (EVs) which are secreted into the extracellular space and can be retrieved in bio fluids [1], including blood [2] and CSF [3]. It is known that EVs mediate the interactions of nervous system cells among themselves, as well as the communication of peripheral organs with the CNS [4][5] Neurons, astrocytes, oligodendrocytes, and microglial cells release EVs and exchange signal molecules through them [6].
EVs have an important role in promoting neural development, regulating the progression of inflammation, and altering tumour characteristics [7][8][9]. Alterations in EVs’ signalling, especially changes in miRNA expression, or the movement of inflammatory molecules may induce variations in the physiological microenvironment, which are closely associated with the degree of central nervous system (CNS) injury [10]. EVs are able to pass the BBB to enter the brain from the periphery or to exit via the circulating [11] CSF or the lymphatic system; due to this, they may be studied as potential biomarkers or therapeutic carriers of CNS diseases [12].
Different studies have highlighted the great potential of the EVs in CNS diseases to play a dual role: on the one hand, cells use EVs to remove toxic proteins and aggregates from their cytoplasm; on the other, these EVs can interact with healthy cells, delivering their toxic cargoes and spreading disease [13]. In the CNS, EVs have been suggested to be potential carriers in the intercellular delivery of misfolded proteins associated with neurodegenerative disorders, such as tau and amyloid β (Ab) in AD, asynuclein in PD, SOD1 in amyotrophic lateral sclerosis, and huntingtin in Huntington’s disease [14][15][16][17][18]. Thus, these recent findings have opened up avenues for the exploitation of these EVs, which may serve as potential biomarkers for different chronic neurodegenerative diseases [19].
Extracting EVs from peripheral blood for the early diagnosis, progression monitoring, and prognosis assessment of CNS diseases may be a safer and more sensitive non-invasive method compared to a “cerebrospinal fluid biopsy” [20][21][22]. Therefore, EVs, serving as biomarkers, reflect changes in the CNS microenvironment, offering new insights for the diagnosis and treatment of CNS diseases [23].
EVs represent the fingerprints of their cells of origin, they can contain and transfer complex molecular cargoes typical of their cells of origin, such as proteins, lipids, carbohydrates, and metabolites, to recipient cells. EVs are also enriched in non-coding RNAs (e.g., microRNAs, lncRNAs, and circRNA), which are formerly considered as cell-intrinsic regulators of CNS functions and pathologies, thus representing a new layer of regulation in the cell-to-cell communication [24].
MicroRNAs (miRNAs) are small non-coding RNAs with a unique ability to control the transcriptomic profile by binding to complementary regulatory RNA sequences. The ability of miRNAs to increase (proinflammatory miRNAs) or reduce (anti-inflammatory miRNAs) inflammatory signalling within the central nervous system is an area of ongoing research, particularly in the context of disorders that feature neuroinflammation, including neurodegenerative diseases [25].
EVs are highly enriched in miRNAs [25]. Recent findings have provided further evidence for the emerging roles of miRNAs in neural development, homeostasis, neuron-glia communications, CNS health, and a range of physiological functions [24]. Table 1 summarizes some of the most important miRNAs contained in EVs and their various functions in brain cells.
Long Non-Coding RNAs (LncRNAs) are also contained in EVs. LncRNAs are molecules that play a key role in the regulation of a wide range of cellular processes, acting as chromatin regulators and regulating gene expression at the transcriptional and post-transcriptional levels [35]; they are a highly heterogeneous class of RNA molecules of more than 200 nucleotides in length with no protein-coding capacity. They are involved in the control of gene expression at multiple levels, such as nuclear architecture, transcription regulation, mRNA splicing, and mRNA stability. Increasing evidence has revealed that lncRNAs can act as ceRNAs via competitively sponging miRNAs to regulate neuroinflammation in several neurodegenerative diseases [36].
Canseco-Rodriguez et al. [37] have described the LncRNA in Alzheimer diseases, and Wang and colleagues have investigated their involvement in Parkinson’s disease [38].
Liao et al. have discovered that lincRNA-Cox2-siRNA-loaded EVs also decreased LPS-induced microglial proliferation in mice. These findings indicate that the intranasal delivery of EV-loaded small RNA could be developed as a therapeutic for the treatment of a multitude of CNS disorders [39].
In addition to miRNAs and lncRNAs, EVs also contain circRNAs that act like ceRNAs to regulate miRNA function in recipient cells. CeRNAs are contained within EVs, and their specific sorting might have two effects: (i) to discard competitors, which modifies the bioavailability of the related active miRNAs, and (ii) to transfer the competitors into recipient cells in which the amount of active miRNA should be altered [40]. The role of ceRNAs carried by EVs has been intensely studied in the field of cancer research; only a few EV-ceRNAs have been reported in neurodegenerative diseases. A recent study revealed that exosomes contain more circRNAs compared to parental cells and the ratio of circRNA level to linear RNA level in exosomes was approximately six-fold higher than that in cells [17][41][42].
EVs can serve as natural carriers for therapeutic agents and drugs, and have many advantages over conventional nanocarriers, including their low immunogenicity, good biocompatibility, natural blood–brain barrier penetration, and capacity for gene delivery [43][44][45].
Wu and colleagues have studied the capacity of engineered EVs encapsulated with Bryostatin-1, a natural compound with remarkable anti-inflammation ability, to reduce neuroinflamamtion [46]. Moreover, engineered EVs charged with nerve growth factor and curcumin, significantly improved the microenvironment after injury and promoted the recovery of motor function after spinal cord injury [47].
The applications of EVs have received much attention and different clinical trials have been registered in recent years; Table 2 reports the most significant clinical trials for EVs reported in https://clinicaltrials.gov (accessed 20 January 2024) [48].

2. Neuron-Derived Extracellular Vesicles 

EVs are multifunctional and complex signalling units that can simultaneously supply recipient cells with a variety of possible effectors [56]. The production of neuronal EVs suggests that they are derived from the endosomal multivesicular body (MVB)-dependent exosome pathway, which uses multiple (possibly overlapping) mechanisms to bud vesicles into the endosomal lumen. Selective cargo loading of neuronal EVs by cone-shaped lipids such as ceramide can occur in both an ESCRT-dependent and ESCRT-independent manner. The best-studied mechanisms are based on ESCRT proteins. The endosomal sorting complex required for the transport (ESCRT) pathway comprises five distinct protein complexes, referred to numerically as ESCRT-0, -I, -II, -III, and the AAA ATPase Vps4 complex. Of these, the ESCRT-0, ESCRT-I, and ESCRT-II protein complexes bundle ubiquitinated cargoes as they curl around membranes, then recruit ESCRT-III components to form a helical polymer that drives the cleavage of the intraluminal vesicle bud in the MVB. While ESCRT’s molecular activities are interesting in explaining their formation, ESCRT components may not always be necessary for EV release. The enzyme sphingomyelinase plays an important role in EV release and can act simultaneously with or independently of ESCRT. There are two types of sphingomyelinases. Neutral sphingomyelinase (n-SMase) cleaves sphingomyelin to release ceramide, which clusters into membrane microdomains that promote inward budding. Acid sphingomyelinase (a-SMase) plays an important housekeeping role in sphingolipid metabolism and membrane turnover. It has also been implicated in the cellular stress response. It can be preferentially transported to the outer leaflet of the cell membrane under conditions of cellular stress. Activated factor VII (FVIIa) induces the release of EVs from the endothelium. FVIIa-released EVs become enriched with phosphatidylserine (PS) and contribute to the haemostatic effect of FVIIa in thrombocytopenia and haemophilia. In the brains of Alzheimer’s patients, for example, the expression levels of a-SMase are increased and the enzymatic activity is abnormally high [57][58][59][60]. It is unclear how cargo is selected during EV biogenesis. It is regulated by post-translational modifications like ubiquitination and sumoylation and seems to rely on interaction with microdomains that are rich in cholesterol and tetraspanin [56]. Given the morphology and compartmentalisation of neurons, understanding the functions of EVs requires knowing from which part of the neuron the EVs are released. Several studies show that EV cargoes and/or MVBs accumulate in the somatodendritic compartment [57]. There is extensive evidence for the neuronal accumulation of EVs in the somatodendritic compartments of mammalian cortical and hippocampal neurons. The superfamily of proteins called tetraspanins, which organises microdomains in the plasma membrane, has a high concentration of exosomes. The tetraspanins CD9, CD63, CD81, and CD151 are involved in exosome biogenesis, protein loading, and sorting cargo into exosomes [61][62]. Furthermore, exosomes are secreted by mature neurons at the soma and dendritic shafts levels, a process that may be part of the physiology of differentiated neurons rather than growth cone development [63]. MVB accumulates in the dendrites of pyramidal, Purkinje, and cortical neurons, suggesting they are released from these sites. Notably, in mammals, a direct mechanism for their preferential release from dendrites is suggested by the movement and local translation of Arc mRNA into dendrites in response to activity-dependent cues [64]. Importantly, EVs’ secretion by neurons may be regulated process that is induced by high K+-induced depolarisation, Gamma-aminobutyric acid type A receptor (GABAAR) antagonists, and/or blocked by NMDA receptor blockers [64][65]. There is also evidence that an enhancement in EVs’ secretion is due to an increase in intracellular calcium [62][65]. The Wnt morphogens family orchestrate a myriad of developmental processes, including the control of cell proliferation and migration and cytoskeletal remodelling. Wnts also coordinate key aspects of the nervous system, regulating neural stem cell proliferation, axon pathfinding, synapse differentiation and plasticity, and learning [66]. Wnts activate a variety of intracellular signalling pathways, the most studied of which involves Wnt ligands binding to the Frizzled (Fz) family of serpentine receptors. The activation of Fz receptors in turn stabilises cytoplasmic β-catenin, which enters the nucleus and regulates gene expression. Other Wnt pathways that have been studied include those involving GSK3-β, which acts through a non-genomic mechanism by phosphorylating microtubule-associated proteins to regulate microtubule stability, as well as mechanisms activated by Wnt ligands such as the planar cell polarity (PCP) pathway and the Wnt/Ca++ pathway [67]. Wnts are one of the first molecules identified as being secreted by EVs and to have a signalling function during development, and are among the molecules expressed and incorporated into neuronal EVs. EVs that are taken up influence a wide range of cellular processes, including neuronal activation, axon guidance, synapse formation, maintenance of dendritic spines, synapse elimination, brain development, and cell expression [66]. Over the years, several molecules contained in neuronal EVs have been studied, including recent studies indicating that Wnt-z signalling is also important for synaptogenesis, synapse and dendrite maintenance, spatial learning and memory, and the formation of hippocampal long-term potentiation (LTP) [68][69]. Other studies have shown that the secretion of PRR7 by neurons on exosomes is activity dependent. Proline-rich 7 (PRR7) is a proline-rich type 1 transmembrane protein first identified as a protein enriched in the postsynaptic density, and these findings highlight the signalling function of neuronal exosomes in synapse maintenance in central neurons [70]. PRR7 functions as a novel Wnt inhibitor in synapse regulation by inhibiting Wnt secretion by exosomes. One of the molecules consistently found in neuronal exosome preparations are α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptors control synaptic transmission and are the main substrates for synaptic plasticity. Glutamatergic neurons form AMPA receptor-containing exosomes following bursts of synaptic activity or ionomycin-induced increases in cytosolic calcium levels. They may contribute to neuronal excitability in recipient neurons. However, the role of exosomal AMPA receptors is currently completely unknown [71].
In addition, EVs transport a variety of molecules that regulate synaptic plasticity. These molecules include endocannabinoids, which affect synaptic functions in both short- and long-term forms of plasticity [72]; the Eph receptor tyrosine kinase and its membrane-bound ephrin ligands, which play a critical role in axon guidance and specific synapse formation [73]; and the neurotrophin receptor p75, which mediates multiple signalling pathways for neurite outgrowth, neuronal survival, and death [74].
miRNAs are one of the most studied categories of molecules transported by EVs. These molecules are non-coding single-stranded RNAs with 19–24 nucleotides directly which are involved in post-transcriptional gene silencing [75]. Several reports indicate that neurons may secrete different types of miRNAs, including miR-124, miR-21-5p, and miR132, which are subsequently taken up by microglia, astrocytes, or endothelial cells [76][77]. These exosome-derived miRNAs influence a variety of processes in the recipient cells, including the modulation of microglial activity, pro-inflammatory responses, gene transcription in astrocytes, and brain vascular integrity. Antoniou et al. showed that the brain-derived neurotrophic factor (BDNF) promotes the sorting of miRNAs into neuronal exosomes, which in turn stimulates the formation of excitatory synapses in recipient neurons [78]. Much less is known about the mechanisms by which neurons take up neuronal exosomes.
According to a number of studies, synaptic clefts appear to be too small for EVs to freely enter and diffuse. For this reason, neuronal exosomes are most likely to be taken up at non-synaptic sites, including the extra-synaptic membrane area in dendrites, axons, and soma [65]. Under normal conditions, neuronal EVs are taken up by neighbouring neurons in a juxtracrine and autocrine manner. Certain conditions, such as extracellular space expansion and/or excessive secretion, cause small neuronal EVs to diffuse further away before being taken up by distant neurons. However, ageing causes shrinkage of the ECS, which may restrict the movement of small EVs and interfere with exosome-mediated intercellular communication.
Characterising EVs from the CNS is challenging because neurons generally release low levels of EVs. However, several studies have identified proteomic signatures of EVs that can help identify their most likely origin as being the CNS. Hornung et al. investigated putative neuron-derived exosomes obtained by immunoprecipitation using antibodies directed against the neuronal marker proteins such as NCAM, that is a neuronal cell adhesion protein that belongs to the immunoglobulin superfamily and is involved in cell–cell and cell–matrix interactions. Another neuronal marker protein that Hornung uses is L1CAM, which is an axonal glycoprotein that is essential for the development of the nervous system [79]. However, no cell subtype-specific EV markers have been identified in different neuronal and glial cell populations. Exosome-mediated communication may facilitate the anterograde and retrograde transfer of information across synapses. Exosomes that have been internalised are likely to alter post-transcriptional mRNA trafficking and translation, as well as induce local changes in synaptic plasticity.
Goldie et al. showed that a specific decrease in miRNA expression was observed in the neurites of potassium-depolarized cells, while exosomes generated by these cells were enriched in miRNAs and microtubule-associated protein 1B (MAP1B) [80]. Four of these miRNAs (miR-638, -149*, -4281, and let-7e) were observed to be negatively regulated by repetitive neuronal depolarisation. Interestingly, these miRNAs regulate the expression of mRNAs involved in synaptic plasticity. MAP1B is known to play an essential role in axon guidance, neuronal regeneration, and neurite branching. MAP1B also regulates the morphology of postsynaptic spines on the dendrites of glutamatergic neurons [80][81]. In addition, the nucleic acid content of neuron-derived EVs (nEVs) appears to be involved in several processes in CNS-like neurological development. For example, miR-132, a common neuronal EV miRNA that targets Ctbp2 (C-terminal binding protein 2), which is involved in regulating the Notch signalling cascade, leads to the accumulation of glial progenitor cells [82]. Neuron-derived extracellular vesicles appear to be involved in retrograde signalling by transferring synaptotagmin4 (Syt4). Syt4 is a membrane-trafficking protein whose expression is regulated by neuronal activity. Stg4 activation induces a signalling cascade involving cAMP, resulting in presynaptic stimulation. Syt4 is found in brain-derived neurotrophic factor-containing vesicles in hippocampal neurons, where it regulates synaptic plasticity and memory formation.
In addition, the postsynaptic release of Syt4-containing exosomes may regulate presynaptic quantal release of neurotransmitters, thereby facilitating synaptic tuning [83][84].
The presence of AMPA receptors in neuron-derived EVs strongly suggests that they have a role in modulating synaptic plasticity. As exosomes can fuse with the cell membrane of postsynaptic neurons, adding functional AMPA receptors to the postsynaptic button will further modulate synaptic strength. The presence of glutamate receptor subunits in neuronal exosomes implies that other ion channels may also travel between neurons, influencing their intrinsic properties [85].
Neurons and astrocytes communicate with through a variety of mechanisms, including exosome-mediated miRNAs transfer. This can regulate protein expression in parasynaptic astrocytes, which in turn can modulate synaptic function and neurotransmission. For example, exosomes carrying small RNAs and miR-124a have been isolated from neuron-conditioned media. They have been shown to be internalised by primary astrocytes. This increases the expression of miR-124a and glutamate transporter 1 (GLT-1) protein in the targeted cells [86]. GLT-1 (also known as excitatory amino acid transporter 2 (EAAT-2)) is crucial for the homeostatic maintenance of synaptic glutamate levels and the prevention of neuronal excitotoxicity [87]. As a result, the cargo of neuronal exosomes may contain complementary combinations of proteins and miRNAs that help astrocytes to maintain the homeostasis of neurotransmission in the CNS [88]. Neuron–microglia communication also occurs via neuron-derived exosome secretion. EVs can stimulate synaptic pruning by upregulating complement factors in microglia [81]. Bahrini et al. [89] induced neuronal degeneration after stimulating neuronal differentiation and synapse formation in PC12 cells. When PC12 cells were co-cultured with a mouse microglial cell line (MG6), microglia engulfed and phagocytized PC12 neurites.
After depolarisation, the MG6 cells were also pre-incubated with exosomes derived from differentiated PC12 neurons, indicating an increased clearance of degenerating neurites. These findings suggest that neuron-derived exosomes increased the expression levels of complement component 3 mRNA expression in MG6 cells rather than the direct transfer of C3 mRNA from PC12 cells [89]. These findings highlight the role of exosomes in the regulation of synapse elimination and reveal a novel mechanism by which active synapses promote the pruning of inactive ones by stimulating microglial phagocytosis with exosomes.

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