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Communication between neurons and glia significantly influences the development maturation, plasticity, and disease progressions of the nervous system. As a new signaling modality, extracellular vesicles display a diverse role for robust functional regulation of neurons through their protein and nucleic acid cargoes. This review highlights recent breakthroughs in the research of signaling mechanisms between glia and neurons mediated by extracellular vesicles that are important for neural development, axonal maintenance, synaptic functions, and disease progression in the mammalian nervous system. We will discuss the biological roles of extracellular vesicles released from neurons, astroglia, microglia, and oligodendroglia in the nervous system and their implications in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition. [ABSTRACT FROM AUTHOR]

Background: We recently demonstrated that large extracellular vesicles (EVs) released by Aβ‐loaded microglia and carrying Aβ (Aβ‐EVs) propagate synaptic dysfunction in the mouse brain by moving at the axon surface (Gabrielli et al., Brain, 2022; Falcicchia et al., Brain Commun, 2023). Compared to ctrl‐EVs, not carrying Aβ, a higher number of Aβ‐EVs move along axons and travel longer distances through a yet undefined mechanism. Our previous work indicates that large EVs motion can be passively driven by neurons, via EV interaction with a neuronal receptor linked to the cytoskeleton, or may happen autonomously when EVs contain actin filaments and ATP in their lumen. To get insights into the mechanisms underlying higher extracellular Aβ‐EVs motion, we here analysed microglial EVs proteome. Method: Aβ‐EVs were obtained from primary microglia exposed to Aβ42. High‐resolution accurate‐mass spectrometry SWATH™‐MS followed by DIA‐NN quantitative analysis was employed to identify differentially expressed proteins in Aβ‐ vs. ctrl‐EVs, which may justify Aβ‐EVs empowered motility and describe the molecular mechanisms underlying EVs extracellular motion. Western blot and optical manipulation coupled to time‐lapse imaging were also employed to explore the involvement of additional candidate molecules, such as transglutaminase 2 (TG2). Result: A total of 148 proteins were upregulated in Aβ‐ compared to ctrl‐EVs, while 169 were downregulated. Panther GO analysis showed that terms enriched in large Aβ‐EVs include cytoskeletal protein binding (GO:0008092) and ATP hydrolysis activity (GO:0016887), suggesting that a higher fraction of Aβ‐EVs may undergo independent motion. STRING analysis revealed a high protein‐protein interaction (PPI) among Aβ‐EVs enriched molecules, some of which are differentially expressed also in EVs from AD/MCI patients or AD mouse models, validating the relevance of our findings. Conclusion: Our data suggest that Aβ‐EVs higher motility and capability to propagate synaptic dysfunction may be due to their augmented capacity to undergo active motion, and identify novel proteins potentially involved in EVs motion. Further analysis will be necessary to validate these findings in AD. Fundings: 2018‐AARF‐588984, Horizon2020#874721PREMSTEM. [ABSTRACT FROM AUTHOR]

Extensive evidence indicates that the activation of the P2X7 receptor (P2X7R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X7R-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2X7R activation on extracellular vesicle release and their activities. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is considered by many to be a synaptic failure. Synaptic function is in fact deeply affected in the very early disease phases and recognized as the main cause of AD-related cognitive impairment. While the reciprocal involvement of amyloid beta (Aβ) and tau peptides in these processes is under intense investigation, the crucial role of extracellular vesicles (EVs) released by different brain cells as vehicles for these molecules and as mediators of early synaptic alterations is gaining more and more ground in the field. In this review, we will summarize the current literature on the contribution of EVs derived from distinct brain cells to neuronal alterations and build a working model for EV-mediated propagation of synaptic dysfunction in early AD. A deeper understanding of EV–neuron interaction will provide useful targets for the development of novel therapeutic approaches aimed at hampering AD progression. [ABSTRACT FROM AUTHOR]

One of the major challenges in multiple sclerosis (MS) research is developing simple and reliable fluid body biomarkers for disease diagnosis, prognosis, and treatment outcomes.[1] Extracellular vesicles (EVs) produced in brain cross the blood-brain barrier and transfer parental cell lineage markers as well as transcripts/proteins/lipids that can inform about the status of brain tissue to peripheral body fluids. Changes in specific microRNAs were identified in MS patients versus healthy subjects but with low reproducibility among studies,[2] thus questioning whether plasma EVs profiling may help monitoring disease activity in MS patients. [Extracted from the article]

Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD. [ABSTRACT FROM AUTHOR]