{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T15:13:01Z","timestamp":1793459581601,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Mo2017\/2 and Mo2017\/3"],"award-info":[{"award-number":["Mo2017\/2 and Mo2017\/3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Interdisciplinary Center for Clinical Research of the Medical Faculty Jena,  (IZKF)","award":["FF05"],"award-info":[{"award-number":["FF05"]}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["CVU: 446429"],"award-info":[{"award-number":["CVU: 446429"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer\u2019s disease, Parkinson\u2019s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL\/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-\u03b2, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.<\/jats:p>","DOI":"10.3390\/cells11040625","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T05:14:43Z","timestamp":1644556483000},"page":"625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7348-059X","authenticated-orcid":false,"given":"Diana M.","family":"Morales-Prieto","sequence":"first","affiliation":[{"name":"Placenta Lab, Department of Obstetrics, Jena University Hospital, 07747 Jena, Germany"},{"name":"RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4093-1419","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Murrieta-Coxca","sequence":"additional","affiliation":[{"name":"Placenta Lab, Department of Obstetrics, Jena University Hospital, 07747 Jena, Germany"},{"name":"RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Stojiljkovic","sequence":"additional","affiliation":[{"name":"Hans-Berger Department of Neurology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Diezel","sequence":"additional","affiliation":[{"name":"RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"FLI Leibniz Institute for Age Research, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priska E.","family":"Streicher","sequence":"additional","affiliation":[{"name":"Placenta Lab, Department of Obstetrics, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian A.","family":"Henao-Restrepo","sequence":"additional","affiliation":[{"name":"Placenta Lab, Department of Obstetrics, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"R\u00f6stel","sequence":"additional","affiliation":[{"name":"Department for Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-5995","authenticated-orcid":false,"given":"Julia","family":"Lindner","sequence":"additional","affiliation":[{"name":"Hans-Berger Department of Neurology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-4105","authenticated-orcid":false,"given":"Otto W.","family":"Witte","sequence":"additional","affiliation":[{"name":"Hans-Berger Department of Neurology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3201-2375","authenticated-orcid":false,"given":"Sebastian","family":"Weis","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Natural Product Research and Infection Biology, Hans Kn\u00f6ll Institute, 07745 Jena, Germany"},{"name":"Institute for Infectious Disease and Infection Control, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2289-0126","authenticated-orcid":false,"given":"Christian","family":"Schmeer","sequence":"additional","affiliation":[{"name":"Hans-Berger Department of Neurology, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manja","family":"Marz","sequence":"additional","affiliation":[{"name":"RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University Jena, 07743 Jena, Germany"},{"name":"FLI Leibniz Institute for Age Research, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1038\/sj.leu.2404296","article-title":"Membrane-derived microvesicles: Important and underappreciated mediators of cell-to-cell communication","volume":"20","author":"Ratajczak","year":"2006","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.cell.2017.11.042","article-title":"Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner","volume":"172","author":"Thion","year":"2018","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12974-017-1038-8","article-title":"In vivo evidence for the contribution of peripheral circulating inflammatory exosomes to neuroinflammation","volume":"15","author":"Li","year":"2018","journal-title":"J. NeuroInflamm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1159\/000156474","article-title":"Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress","volume":"15","author":"Sparkman","year":"2008","journal-title":"Neuroimmunomodulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nri855","article-title":"Exosomes: Composition, biogenesis and function","volume":"2","author":"Thery","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1126\/science.aag2590","article-title":"How neuroinflammation contributes to neurodegeneration","volume":"353","author":"Ransohoff","year":"2016","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1038\/s41598-017-01386-z","article-title":"Age-Related Changes in Plasma Extracellular Vesicle Characteristics and Internalization by Leukocytes","volume":"7","author":"Eitan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.addr.2012.07.010","article-title":"The role of exosomes and microRNAs in senescence and aging","volume":"65","author":"Xu","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1089\/ten.tea.2016.0525","article-title":"MicroRNA-183-5p Increases with Age in Bone-Derived Extracellular Vesicles, Suppresses Bone Marrow Stromal (Stem) Cell Proliferation, and Induces Stem Cell Senescence","volume":"23","author":"Davis","year":"2017","journal-title":"Tissue Eng. Part A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/nature23282","article-title":"Hypothalamic stem cells control ageing speed partly through exosomal miRNAs","volume":"548","author":"Zhang","year":"2017","journal-title":"Nature"},{"key":"ref_11","first-page":"136","article-title":"Role of pro-inflammatory cytokines released from microglia in Alzheimer\u2019s disease","volume":"3","author":"Wang","year":"2015","journal-title":"Ann. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12524","DOI":"10.1073\/pnas.1902672116","article-title":"Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment","volume":"116","author":"Gan","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neurobiolaging.2018.10.007","article-title":"Phenotypic and functional differences between senescent and aged murine microglia","volume":"74","author":"Stojiljkovic","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"546415","DOI":"10.3389\/fimmu.2020.546415","article-title":"Memory-Like Responses of Brain Microglia Are Controlled by Developmental State and Pathogen Dose","volume":"11","author":"Lajqi","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Sharma, P., Bullock, K.M., Hansen, K.M., Ludwig, N., and Whiteside, T.L. (2020). Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124407"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chaiwangyen, W., Murrieta-Coxca, J.M., Favaro, R.R., Photini, S.M., Gutierrez-Samudio, R.N., Schleussner, E., Markert, U.R., and Morales-Prieto, D.M. (2020). MiR-519d-3p in Trophoblastic Cells: Effects, Targets and Transfer to Allogeneic Immune Cells via Extracellular Vesicles. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103458"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.trsl.2016.02.012","article-title":"MicroRNA-141 is upregulated in preeclamptic placentae and regulates trophoblast invasion and intercellular communication","volume":"172","author":"Chaiwangyen","year":"2016","journal-title":"Transl. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27066","DOI":"10.3402\/jev.v4.27066","article-title":"Biological properties of extracellular vesicles and their physiological functions","volume":"4","author":"Siljander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1002\/1873-3468.14074","article-title":"Extracellular vesicles and intercellular communication in the central nervous system","volume":"595","author":"Sheridan","year":"2021","journal-title":"FEBS Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.15252\/emmm.201606271","article-title":"Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles","volume":"8","author":"Balusu","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1800149","DOI":"10.1002\/pmic.201800149","article-title":"Exosomes in Inflammation and Inflammatory Disease","volume":"19","author":"Chan","year":"2019","journal-title":"Proteomics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/978-1-62703-520-0_21","article-title":"Preparation of rodent primary cultures for neuron-glia, mixed glia, enriched microglia, and reconstituted cultures with microglia","volume":"1041","author":"Chen","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Caruso Bavisotto, C., Scalia, F., Marino Gammazza, A., Carlisi, D., Bucchieri, F., Conway de Macario, E., Macario, A.J.L., Cappello, F., and Campanella, C. (2019). Extracellular Vesicle-Mediated Cell(-)Cell Communication in the Nervous System: Focus on Neurological Diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020434"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Pegtel, D.M., Peferoen, L., and Amor, S. (2014). Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369.","DOI":"10.1098\/rstb.2013.0516"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3389\/fnagi.2019.00232","article-title":"Exosome Determinants of Physiological Aging and Age-Related Neurodegenerative Diseases","volume":"11","author":"Fenoglio","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98","DOI":"10.21037\/sci.2017.12.03","article-title":"Extracellular vesicles and aging","volume":"4","author":"Robbins","year":"2017","journal-title":"Stem Cell Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.ijge.2018.03.013","article-title":"The Comparison of Exosome and Exosomal Cytokines between Young and Old Individuals with or without Gastric Cancer","volume":"12","author":"Im","year":"2018","journal-title":"Int. J. Gerontol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12195-016-0458-3","article-title":"Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro","volume":"9","author":"Chen","year":"2016","journal-title":"Cell. Mol. Bioeng."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1093\/ijnp\/pyy098","article-title":"Small Extracellular Vesicles in Rat Serum Contain Astrocyte-Derived Protein Biomarkers of Repetitive Stress","volume":"22","author":"Sandoval","year":"2019","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.addr.2021.05.006","article-title":"Extracellular vesicles for the treatment of central nervous system diseases","volume":"174","author":"Gratpain","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/s41591-019-0440-4","article-title":"Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1","volume":"25","author":"Yousef","year":"2019","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26238","DOI":"10.3402\/jev.v4.26238","article-title":"Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice","volume":"4","author":"Imai","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26316","DOI":"10.3402\/jev.v4.26316","article-title":"Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting","volume":"4","author":"Wiklander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e12085","DOI":"10.1002\/jev2.12085","article-title":"Biodistribution of extracellular vesicles following administration into animals: A systematic review","volume":"10","author":"Kang","year":"2021","journal-title":"J. Extracell. Vesicles"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nn.4132","article-title":"Depletion of microglia and inhibition of exosome synthesis halt tau propagation","volume":"18","author":"Asai","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9533","DOI":"10.1038\/s41598-020-66434-7","article-title":"Systematic Evaluation of PKH Labelling on Extracellular Vesicle Size by Nanoparticle Tracking Analysis","volume":"10","author":"Dehghani","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nm.3569","article-title":"Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice","volume":"20","author":"Villeda","year":"2014","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.18632\/aging.100865","article-title":"Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles","volume":"8","author":"Weilner","year":"2016","journal-title":"Aging"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sieber, M.W., Claus, R.A., Witte, O.W., and Frahm, C. (2011). Attenuated inflammatory response in aged mice brains following stroke. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026288"},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1242\/jcs.074088","article-title":"Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis","volume":"124","author":"Fitzner","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Saint-Pol, J., Gosselet, F., Duban-Deweer, S., Pottiez, G., and Karamanos, Y. (2020). Targeting and Crossing the Blood-Brain Barrier with Extracellular Vesicles. Cells, 9.","DOI":"10.3390\/cells9040851"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/4\/625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:17:20Z","timestamp":1760134640000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/4\/625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,11]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["cells11040625"],"URL":"https:\/\/doi.org\/10.3390\/cells11040625","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/471409","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,11]]}}}