{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:31:21Z","timestamp":1792071081896,"version":"4.4.0"},"reference-count":89,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,4]],"date-time":"2020-07-04T00:00:00Z","timestamp":1593820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer\u2019s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs\/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV\/NEV uptake, as effectors of neurodegeneration in AD.<\/jats:p>","DOI":"10.3390\/cells9071618","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T09:49:11Z","timestamp":1594028951000},"page":"1618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer\u2019s Disease Patients Effect Complement-Mediated Neurotoxicity"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-965X","authenticated-orcid":false,"given":"Carlos J.","family":"Nogueras-Ortiz","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Mahairaki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0201-0248","authenticated-orcid":false,"given":"Francheska","family":"Delgado-Peraza","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debamitra","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5335-8346","authenticated-orcid":false,"given":"Konstantinos","family":"Avgerinos","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5190-9500","authenticated-orcid":false,"given":"Erden","family":"Eren","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-6144","authenticated-orcid":false,"given":"Matthew","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Goetzl","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, CA 94143, USA"},{"name":"San Francisco Campus for Jewish Living, San Francisco, CA 94112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P.","family":"Mattson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2181-3118","authenticated-orcid":false,"given":"Dimitrios","family":"Kapogiannis","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA\/NIH), Baltimore, MD 21224, USA"},{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.cell.2015.12.056","article-title":"The Cellular Phase of Alzheimer\u2019s Disease","volume":"164","author":"Karran","year":"2016","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.immuni.2019.03.016","article-title":"Immune Signaling in Neurodegeneration","volume":"50","author":"Hammond","year":"2019","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1074\/jbc.M110.135244","article-title":"Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity","volume":"286","author":"Maezawa","year":"2011","journal-title":"J. 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