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Tau pathology can spread via extracellular vesicles, such as exosomes. The cargo of neuron-derived small extracellular vesicles (NDEVs) from individuals with DS contains p-Tau at an early age. The goal of the study was to investigate whether NDEVs isolated from the blood of individuals with DS can spread Tau pathology in the brain of wildtype mice. We purified NDEVs from the plasma of patients with DS-AD and controls and injected small quantities using stereotaxic surgery into the dorsal hippocampus of adult wildtype mice. Seeding competent Tau conformers were amplified in vitro from DS-AD NDEVs but not NDEVs from controls. One month or 4 months post-injection, we examined Tau pathology in mouse brains. We found abundant p-Tau immunostaining in the hippocampus of the mice injected with DS-AD NDEVs compared to injections of age-matched control NDEVs. Double labeling with neuronal and glial markers showed that p-Tau staining was largely found in neurons and, to a lesser extent, in glial cells and that p-Tau immunostaining was spreading along the corpus callosum and the medio-lateral axis of the hippocampus. These studies demonstrate that NDEVs from DS-AD patients exhibit Tau seeding capacity and give rise to tangle-like intracellular inclusions.<\/jats:p>","DOI":"10.3390\/jcm10173931","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T08:42:32Z","timestamp":1630399352000},"page":"3931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain"],"prefix":"10.3390","volume":"10","author":[{"given":"Aur\u00e9lie","family":"Ledreux","sequence":"first","affiliation":[{"name":"Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Thomas","sequence":"additional","affiliation":[{"name":"Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric D.","family":"Hamlett","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Trautman","sequence":"additional","affiliation":[{"name":"Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anah","family":"Gilmore","sequence":"additional","affiliation":[{"name":"Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Rickman Hager","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Paredes","sequence":"additional","affiliation":[{"name":"Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-5927","authenticated-orcid":false,"given":"Martin","family":"Margittai","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fortea","sequence":"additional","affiliation":[{"name":"Hospital de la Santa Creu i Sant Pau and Catalan Down Syndrome Foundation, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Charlotte","family":"Granholm","sequence":"additional","affiliation":[{"name":"Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/ajmg.a.38512","article-title":"Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines","volume":"176","author":"Capone","year":"2018","journal-title":"Am. 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