{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T06:56:23Z","timestamp":1773212183243,"version":"3.50.1"},"reference-count":112,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The central nervous system (CNS) is the most complex structure in the body, consisting of multiple cell types with distinct morphology and function. Development of the neuronal circuit and its function rely on a continuous crosstalk between neurons and non-neural cells. It has been widely accepted that extracellular vesicles (EVs), mainly exosomes, are effective entities responsible for intercellular CNS communication. They contain membrane and cytoplasmic proteins, lipids, non-coding RNAs, microRNAs and mRNAs. Their cargo modulates gene and protein expression in recipient cells. Several lines of evidence indicate that EVs play a role in modifying signal transduction with subsequent physiological changes in neurogenesis, gliogenesis, synaptogenesis and network circuit formation and activity, as well as synaptic pruning and myelination. Several studies demonstrate that neural and non-neural EVs play an important role in physiological and pathological neurodevelopment. The present review discusses the role of EVs in various neurodevelopmental disorders and the prospects of using EVs as disease biomarkers and therapeutics.<\/jats:p>","DOI":"10.3390\/ijms21249428","type":"journal-article","created":{"date-parts":[[2020,12,13]],"date-time":"2020-12-13T23:39:36Z","timestamp":1607902776000},"page":"9428","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Extracellular Vesicles in CNS Developmental Disorders"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0655-1423","authenticated-orcid":false,"given":"Ana Rita","family":"Gomes","sequence":"first","affiliation":[{"name":"Department of Bioengineering and IBB\u2014Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"},{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht, 6200 MD Maastricht, The Netherlands"},{"name":"GKC-Rett Expertise Centre, Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3560-2058","authenticated-orcid":false,"given":"Nasim Bahram","family":"Sangani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht, 6200 MD Maastricht, The Netherlands"},{"name":"GKC-Rett Expertise Centre, Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-2832","authenticated-orcid":false,"given":"Tiago G.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and IBB\u2014Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6270-4455","authenticated-orcid":false,"given":"M. Margarida","family":"Diogo","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and IBB\u2014Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9154-1395","authenticated-orcid":false,"given":"Leopold M. G.","family":"Curfs","sequence":"additional","affiliation":[{"name":"GKC-Rett Expertise Centre, Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands"}]},{"given":"Chris P.","family":"Reutelingsperger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht, 6200 MD Maastricht, The Netherlands"},{"name":"GKC-Rett Expertise Centre, Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nrn.2015.29","article-title":"Extracellular vesicles round off communication in the nervous system","volume":"17","author":"Budnik","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.bbamem.2016.02.011","article-title":"Exosomes and other extracellular vesicles in neural cells and neurodegenerative diseases","volume":"1858","author":"Janas","year":"2016","journal-title":"Biochim. Biophys. Acta-Biomembr."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kalra, H., Simpson, R.J., Ji, H., Aikawa, E., Altevogt, P., Askenase, P., Bond, V.C., Borr\u00e0s, F.E., Breakefield, X., and Budnik, V. (2012). Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation. PLoS Biol., 10.","DOI":"10.1371\/journal.pbio.1001450"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20130516","DOI":"10.1098\/rstb.2013.0516","article-title":"Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain","volume":"369","author":"Pegtel","year":"2014","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: Exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev-cellbio-101512-122326","article-title":"Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles","volume":"30","author":"Colombo","year":"2014","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11060-013-1084-8","article-title":"Biogenesis of extracellular vesicles (EV): Exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies","volume":"113","author":"Akers","year":"2013","journal-title":"J. Neurooncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Doyle, L., and Wang, M. (2019). Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells, 8.","DOI":"10.3390\/cells8070727"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25011","DOI":"10.3402\/jev.v3.25011","article-title":"Comparative analysis of discrete exosome fractions obtained by differential centrifugation","volume":"3","author":"Jeppesen","year":"2014","journal-title":"J. Extracell. Vesicles"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1800021","DOI":"10.1002\/smtd.201800021","article-title":"Methods and Technologies for Exosome Isolation and Characterization","volume":"2","author":"Zhang","year":"2018","journal-title":"Small Methods"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"262-262.e1","DOI":"10.1016\/j.cell.2020.04.054","article-title":"SnapShot: Extracellular Vesicles","volume":"182","author":"Cocozza","year":"2020","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3402\/jev.v2i0.20677","article-title":"Distinct RNA profiles in subpopulations of extracellular vesicles: Apoptotic bodies, microvesicles and exosomes","volume":"2","author":"Crescitelli","year":"2013","journal-title":"J. Extracell. Vesicles"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.ceb.2011.04.008","article-title":"MVB Vesicle Formation: ESCRT-Dependent, ESCRT-Independent and Everything in Between","volume":"23","author":"Babst","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1126\/science.1153124","article-title":"Ceramide triggers budding of exosome vesicles into multivesicular endosomes","volume":"319","author":"Trajkovic","year":"2008","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Marzano, M., Bejoy, J., Cheerathodi, M.R., Sun, L., York, S.B., Zhao, J., Kanekiyo, T., Bu, G., Meckes, D.G., and Li, Y. (2019). Differential Effects of Extracellular Vesicles of Lineage-Specific Human Pluripotent Stem Cells on the Cellular Behaviors of Isogenic Cortical Spheroids. Cells, 8.","DOI":"10.3390\/cells8090993"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1600-0854.2004.00257.x","article-title":"Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner","volume":"6","author":"Savina","year":"2005","journal-title":"Traffic"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.mcn.2005.12.003","article-title":"Exosomes are released by cultured cortical neurones","volume":"31","author":"Lachenal","year":"2006","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"32570","DOI":"10.3402\/jev.v5.32570","article-title":"High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources","volume":"5","author":"Haraszti","year":"2016","journal-title":"J. Extracell. Vesicles"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1194\/jlr.E086173","article-title":"Extracellular vesicles: Lipids as key components of their biogenesis and functions","volume":"59","author":"Record","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7309","DOI":"10.4049\/jimmunol.166.12.7309","article-title":"Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles","volume":"166","author":"Boussac","year":"2001","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"573511","DOI":"10.3389\/fcell.2020.573511","article-title":"Extracellular Vesicles Derived From Apoptotic Cells: An Essential Link between Death and Regeneration","volume":"8","author":"Li","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7105","DOI":"10.1074\/jbc.M112.410944","article-title":"Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1","volume":"288","author":"Morel","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4236","DOI":"10.1038\/s41467-019-11534-w","article-title":"Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS","volume":"10","author":"Men","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/stem.1129","article-title":"Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth","volume":"30","author":"Xin","year":"2012","journal-title":"Stem Cells"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"586","DOI":"10.4103\/1673-5374.266908","article-title":"Extracellular vesicles in the diagnosis and treatment of central nervous system diseases","volume":"15","author":"Shaimardanova","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.neulet.2016.10.042","article-title":"Next-generation sequencing-based small RNA profiling of cerebrospinal fluid exosomes","volume":"636","author":"Yagi","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1242\/jcs.02439","article-title":"Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells","volume":"118","author":"Marzesco","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.mcn.2010.11.004","article-title":"Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity","volume":"46","author":"Lachenal","year":"2011","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7989","DOI":"10.1038\/srep07989","article-title":"Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia","volume":"5","author":"Bahrini","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.cell.2017.12.024","article-title":"The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer","volume":"172","author":"Pastuzyn","year":"2018","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1002\/dneu.20559","article-title":"Regulation of Heat Shock Protein 70 Release in Astrocytes: Role of Signaling Kinases","volume":"67","author":"Taylor","year":"2007","journal-title":"Dev. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7275","DOI":"10.1523\/JNEUROSCI.6476-10.2011","article-title":"Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes","volume":"31","author":"Wang","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Fr\u00fchbeis, C., Fr\u00f6hlich, D., Kuo, W.P., Amphornrat, J., Thilemann, S., Saab, A.S., Kirchhoff, F., M\u00f6bius, W., Goebbels, S., and Nave, K.A. (2013). Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte-Neuron Communication. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001604"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12974-017-0819-4","article-title":"Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury","volume":"14","author":"Kumar","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/emboj.2011.489","article-title":"Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism","volume":"31","author":"Antonucci","year":"2012","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/glia.22772","article-title":"Serotonin stimulates secretion of exosomes from microglia cells","volume":"63","author":"Glebov","year":"2015","journal-title":"Glia"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Schiera, G., Di Liegro, C.M., and Di Liegro, I. (2020). Cell-to-cell communication in learning and memory: From neuro-and glio-transmission to information exchange mediated by extracellular vesicles. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010266"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"16086","DOI":"10.1073\/pnas.1902513116","article-title":"Exosomes regulate neurogenesis and circuit assembly","volume":"116","author":"Sharma","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s12974-018-1275-5","article-title":"Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1\u03b2","volume":"15","author":"Tsilioni","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1002\/dneu.22708","article-title":"Enhanced generation of intraluminal vesicles in neuronal late endosomes in the brain of a Down syndrome mouse model with endosomal dysfunction","volume":"79","author":"Hargash","year":"2019","journal-title":"Dev. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neurobiolaging.2019.07.016","article-title":"A pleiotropic role for exosomes loaded with the amyloid \u03b2 precursor protein carboxyl-terminal fragments in the brain of Down syndrome patients","volume":"84","author":"Gauthier","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.freeradbiomed.2017.08.028","article-title":"Exosomal biomarkers in Down syndrome and Alzheimer\u2019s disease","volume":"114","author":"Hamlett","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/nan.12406","article-title":"The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome","volume":"44","author":"Milenkovic","year":"2018","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.jalz.2016.08.012","article-title":"Neuronal exosomes reveal Alzheimer\u2019s disease biomarkers in Down syndrome","volume":"13","author":"Hamlett","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12974-019-1529-x","article-title":"TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles","volume":"16","author":"Montesinos","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Crenshaw, B.J., Kumar, S., Bell, C.R., Jones, L.B., Williams, S.D., Saldanha, S.N., Joshi, S., Sahu, R., Sims, B., and Matthews, Q.L. (2019). Alcohol Modulates the Biogenesis and Composition of Microglia-Derived Exosomes. Biology, 8.","DOI":"10.3390\/biology8020025"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1111\/acer.14066","article-title":"Ethanol Exposure Increases miR-140 in Extracellular Vesicles: Implications for Fetal Neural Stem Cell Proliferation and Maturation","volume":"43","author":"Tseng","year":"2019","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.3892\/mmr.2020.11194","article-title":"Quantitative proteomic characterization of microvesicles\/exosomes from the cerebrospinal fluid of patients with acute bilirubin encephalopathy","volume":"22","author":"Tan","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13229-018-0240-6","article-title":"Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice","volume":"9","author":"Perets","year":"2018","journal-title":"Mol. Autism"},{"key":"ref_51","first-page":"S49","article-title":"Exosomes derived from adipose mesenchymal stem cells: A potential non-invasive intranasal treatment for autism","volume":"22","author":"Geffen","year":"2020","journal-title":"Cytotherapy"},{"key":"ref_52","first-page":"S49","article-title":"Immuno-Modulation and neuroprotection mediate the therapeutic effect of exosomes in mice model of autism","volume":"22","author":"Geffen","year":"2020","journal-title":"Cytotherapy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/dneu.22712","article-title":"Exosome release and cargo in Down syndrome","volume":"79","author":"Hamlett","year":"2019","journal-title":"Dev. Neurobiol."},{"key":"ref_54","unstructured":"Goetzl, L., and Goetzl, E. (2019). Purification, Extraction and Analyses of Fetal Neurally-Derived Exosomes in Maternal Blood and Neonatal Neurally-Derived Exosomes from Neonatal Blood. (Application No. 16\/068,738), U.S. Patent."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41583-018-0006-3","article-title":"Rett syndrome: Insights into genetic, molecular and circuit mechanisms","volume":"19","author":"Ip","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.neuron.2007.10.001","article-title":"Review the Story of Rett Syndrome: From Clinic to Neurobiology","volume":"56","author":"Chahrour","year":"2007","journal-title":"Neuron"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.cell.2010.10.016","article-title":"A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells","volume":"143","author":"Marchetto","year":"2010","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1073\/pnas.1524013113","article-title":"KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome","volume":"113","author":"Tang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3951","DOI":"10.1002\/cne.24315","article-title":"Structural and functional differences in the barrel cortex of Mecp2 null mice","volume":"525","author":"Lee","year":"2017","journal-title":"J. Comp. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcell.2020.610427","article-title":"Modelling Rett Syndrome with Human Patient-Specific Forebrain Organoids","volume":"8","author":"Gomes","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"214","DOI":"10.4161\/epi.2.4.5212","article-title":"MeCP2 deficiency in the brain decreases BDNF levels by REST\/CoREST-mediated repression and increases TRKB production","volume":"2","author":"Abuhatzira","year":"2007","journal-title":"Epigenetics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.nbd.2008.12.011","article-title":"Bdnf Overexpression in Hippocampal Neurons Prevents Dendritic Atrophy Caused by Rett-Associated MECP2 Mutations","volume":"34","author":"Larimore","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.neuropharm.2013.03.024","article-title":"BDNF deregulation in Rett syndrome","volume":"76","author":"Li","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.exger.2017.08.024","article-title":"Walking Speed Decline in Older Adults is Associated with Elevated Pro-BDNF in Plasma Extracellular Vesicles","volume":"98","author":"Suire","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41380-018-0056-y","article-title":"The ASD Living Biology: From cell proliferation to clinical phenotype","volume":"24","author":"Courchesne","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cell.2015.06.034","article-title":"FOXG1-Dependent Dysregulation of GABA\/Glutamate Neuron Differentiation in Autism Spectrum Disorders","volume":"162","author":"Mariani","year":"2015","journal-title":"Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1212\/WNL.57.2.245","article-title":"Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study","volume":"57","author":"Courchesne","year":"2001","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.bbi.2019.04.037","article-title":"The influence of neuroinflammation in Autism Spectrum Disorder","volume":"79","author":"Matta","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"796","DOI":"10.4103\/1673-5374.268893","article-title":"Exosomes as mediators of neuron-glia communication in neuroinflammation","volume":"15","author":"Pascual","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/ana.20315","article-title":"Neuroglial activation and neuroinflammation in the brain of patients with autism","volume":"57","author":"Vargas","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1742-2094-7-80","article-title":"Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children","volume":"7","author":"Zhang","year":"2010","journal-title":"J. Neuroinflammation"},{"key":"ref_72","first-page":"159","article-title":"The potential neuroprotective role of mesenchymal stem cell-derived exosomes in cerebellar cortex lipopolysaccharide-induced neuroinflammation in rats: A histological and immunohistochemical study","volume":"3","year":"2020","journal-title":"Ultrastruct. Pathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.pnpbp.2018.08.030","article-title":"Cannabidiol as a suggested candidate for treatment of autism spectrum disorder","volume":"89","author":"Poleg","year":"2019","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"213","DOI":"10.15252\/embr.201439668","article-title":"Active endocannabinoids are secreted on the surface of microglial microvesicles","volume":"16","author":"Gabrielli","year":"2015","journal-title":"EMBO Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1096\/fj.201700673r","article-title":"Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons","volume":"32","author":"Huang","year":"2018","journal-title":"FASEB J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/mt.2011.164","article-title":"Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain","volume":"19","author":"Zhuang","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.15252\/embj.201694700","article-title":"Self-organized developmental patterning and differentiation in cerebral organoids","volume":"36","author":"Renner","year":"2017","journal-title":"EMBO J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fbioe.2020.00070","article-title":"Maturation of human pluripotent stem cell-derived cerebellar neurons in the absence of co-culture","volume":"8","author":"Silva","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"13333","DOI":"10.1073\/pnas.93.23.13333","article-title":"Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome","volume":"93","author":"Holtzman","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2174\/1567205012666150921095505","article-title":"Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome","volume":"13","author":"Hamlett","year":"2015","journal-title":"Curr. Alzheimer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0002-9440(10)64538-5","article-title":"Endocytic pathway abnormalities precede amyloid \u03b2 deposition in sporadic alzheimer\u2019s disease and down syndrome: Differential effects of APOE genotype and presenilin mutations","volume":"157","author":"Cataldo","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s40478-017-0466-0","article-title":"Enhanced exosome secretion in Down syndrome brain\u2014A protective mechanism to alleviate neuronal endosomal abnormalities","volume":"5","author":"Gauthier","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"489","DOI":"10.5858\/2001-125-0489-IAAPDO","article-title":"Intraneuronal A\u03b2-amyloid precedes development of amyloid plaques in Down syndrome","volume":"125","author":"Gyure","year":"2001","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.febslet.2014.11.027","article-title":"A potential function for neuronal exosomes: Sequestering intracerebral amyloid-\u03b2 peptide","volume":"589","author":"Yuyama","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1056\/NEJM198906013202203","article-title":"Amyloid A4 and its precursor in Down\u2019s syndrome and Alzheimer\u2019s disease","volume":"320","author":"Baden","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0304-3940(01)01657-3","article-title":"Elevated plasma amyloid b-peptide 1 \u00b1 42 and onset of dementia in adults with Down syndrome","volume":"301","author":"Schupf","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/jnr.490400515","article-title":"Evidence that secretase cleavage of cell surface Alzheimer amyloid precursor occurs after normal endocytic internalization","volume":"40","author":"Refolo","year":"1995","journal-title":"J. Neurosci. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"12922","DOI":"10.1096\/fj.202000823R","article-title":"Extracellular vesicles: Where the amyloid precursor protein carboxyl-terminal fragments accumulate and amyloid-\u03b2 oligomerizes","volume":"34","author":"Kim","year":"2020","journal-title":"FASEB J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41598-017-00682-y","article-title":"Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice","volume":"7","author":"Yin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"541","DOI":"10.3233\/JAD-180776","article-title":"Neuronal exosome-derived human tau is toxic to recipient mouse neurons in vivo","volume":"67","author":"Winston","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1074\/mcp.RA120.002079","article-title":"Dysregulation of exosome cargo by mutant tau expressed in human-induced pluripotent stem cell (iPSC) neurons revealed by proteomics analyses","volume":"19","author":"Podvin","year":"2020","journal-title":"Mol. Cell. Proteom."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"10977","DOI":"10.1074\/jbc.M111.324616","article-title":"Sphingolipid-modulated exosome secretion promotes clearance of amyloid-\u03b2 by microglia","volume":"287","author":"Yuyama","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cotox.2019.08.002","article-title":"Toxicant and teratogenic effects of prenatal alcohol","volume":"14","author":"Mahnke","year":"2019","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s40474-014-0020-8","article-title":"Fetal Alcohol Spectrum Disorders: Recent Neuroimaging Findings","volume":"1","author":"Moore","year":"2014","journal-title":"Curr. Dev. Disord. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.nbd.2005.04.014","article-title":"Role of caspase-3 in ethanol-induced developmental neurodegeneration","volume":"20","author":"Young","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0165-3806(02)00279-1","article-title":"Ethanol-induced apoptotic neurodegeneration in the developing C57BL\/6 mouse brain","volume":"133","author":"Olney","year":"2002","journal-title":"Dev. Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0006-8993(01)03224-3","article-title":"Ethanol-induced alterations of neurotrophin receptor expression on Purkinje cells in the neonatal rat cerebellum","volume":"924","author":"Light","year":"2002","journal-title":"Brain Res."},{"key":"ref_98","first-page":"299","article-title":"Nonprotein-coding RNAs in Fetal Alcohol Spectrum Disorders","volume":"157","author":"Mahnke","year":"2018","journal-title":"Prog. Mol. Biol. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1111\/acer.12139","article-title":"Suppression and epigenetic regulation of miR-9 contributes to ethanol teratology: Evidence from zebrafish and murine fetal neural stem cell models","volume":"37","author":"Balaraman","year":"2013","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"R13","DOI":"10.1186\/gb-2004-5-3-r13","article-title":"Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation","volume":"5","author":"Sempere","year":"2004","journal-title":"Genome Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1242\/bio.20147765","article-title":"MiR-153 targets the nuclear factor-1 family and protects against teratogenic effects of ethanol exposure in fetal neural stem cells","volume":"3","author":"Tsai","year":"2014","journal-title":"Biol. Open"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1096\/fj.11-194464","article-title":"MicroRNAs control neurobehavioral development and function in zebrafish","volume":"26","author":"Tal","year":"2012","journal-title":"FASED J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.siny.2014.12.008","article-title":"The clinical syndrome of bilirubin-induced neurologic dysfunction","volume":"20","author":"Bhutani","year":"2015","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1159\/000495518","article-title":"The Neonatal Acute Bilirubin Encephalopathy Registry (NABER): Background, Aims, and Protocol","volume":"115","author":"Bahr","year":"2019","journal-title":"Neonatology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fphar.2012.00088","article-title":"The evolving landscape of neurotoxicity by unconjugated bilirubin: Role of glial cells and inflammation","volume":"3","author":"Brites","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1056\/NEJMra1308124","article-title":"Bilirubin-Induced Neurologic Damage\u2014Mechanisms and Management Approaches","volume":"369","author":"Watchko","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1007\/s00204-016-1835-3","article-title":"Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells","volume":"91","author":"Qaisiya","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41398-019-0459-9","article-title":"The emerging role of exosomes in mental disorders","volume":"9","author":"Saeedi","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Kwon, S., Shin, S., Do, M., Oh, B.H., Song, Y., Bui, V.D., Lee, E.S., Jo, D.-G., Cho, Y.W., and Kim, D.-H. (2020). Engineering approaches for effective therapeutic applications based on extracellular vesicles. J. Control. Release, 20.","DOI":"10.1016\/j.jconrel.2020.11.062"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"100261","DOI":"10.1016\/j.impact.2020.100261","article-title":"Exosome engineering: Current progress in cargo loading and targeted delivery","volume":"20","author":"Fu","year":"2020","journal-title":"NanoImpact"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jconrel.2017.07.001","article-title":"Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases","volume":"262","author":"Albuquerque","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"553444","DOI":"10.3389\/fcell.2020.553444","article-title":"Scalable Production of Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Under Serum-\/Xeno-Free Conditions in a Microcarrier-Based Bioreactor Culture System","volume":"8","author":"Bernardes","year":"2020","journal-title":"Front. Cell Dev. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9428\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:43:45Z","timestamp":1760179425000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9428"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,11]]},"references-count":112,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21249428"],"URL":"https:\/\/doi.org\/10.3390\/ijms21249428","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,11]]}}}