{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:59Z","timestamp":1787028539295,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T00:00:00Z","timestamp":1713571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIDCR","award":["R01 DE14328"],"award-info":[{"award-number":["R01 DE14328"]}]},{"name":"NIH\/NIDCR","award":["P30EY031631"],"award-info":[{"award-number":["P30EY031631"]}]},{"name":"NIH\/NEI","award":["R01 DE14328"],"award-info":[{"award-number":["R01 DE14328"]}]},{"name":"NIH\/NEI","award":["P30EY031631"],"award-info":[{"award-number":["P30EY031631"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Porphyromonas gingivalis (Pg) and its gingipain proteases contribute to Alzheimer\u2019s disease (AD) pathogenesis through yet unclear mechanisms. Cellular secretion of small extracellular vesicles or exosomes (EXO) increases with aging as part of the senescence-associated secretory phenotype (SASP). We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo. Here, EXO were isolated from the gingiva of mice and humans with\/without periodontitis (PD) to determine their ability to penetrate the blood\u2013brain barrier (BBB) in vitro and in vivo. PD was induced by Pg oral gavage for 6 weeks in C57B6 mice. EXO isolated from the gingiva or brain of donor Pg-infected (PD EXO) or control animals (Con EXO) were characterized by NTA, Western blot, and TEM. Gingival PD EXO or Con EXO were labeled and injected into the gingiva of uninfected WT mouse model. EXO biodistribution in brains was tracked by an in vivo imaging system (IVIS) and confocal microscopy. The effect of human PD EXO on BBB integrity and permeability was examined using TEER and FITC dextran assays in a human in vitro 3D model of the BBB. Pg antigens (RGP and Mfa-1) were detected in EXO derived from gingival and brain tissues of donor Pg-infected mice. Orally injected PD EXO from donor mice penetrated the brains of recipient uninfected mice and colocalized with hippocampal microglial cells. IL-1\u03b2 and IL-6 were expressed in human PD EXO and not in Con EXO. Human PD EXO promoted BBB permeability and penetrated the BBB in vitro. This is the first demonstration that microbial-induced EXO in the oral cavity can disseminate, cross the BBB, and may contribute to AD pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms25084509","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T07:44:09Z","timestamp":1713771849000},"page":"4509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood\u2013Brain Barrier"],"prefix":"10.3390","volume":"25","author":[{"given":"Mahmoud","family":"Elashiry","sequence":"first","affiliation":[{"name":"Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Carroll","sequence":"additional","affiliation":[{"name":"Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2870-4504","authenticated-orcid":false,"given":"Yutao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hamrick","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher W.","family":"Cutler","sequence":"additional","affiliation":[{"name":"Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5034-4109","authenticated-orcid":false,"given":"Ranya","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/alz.12328","article-title":"2021 Alzheimer\u2019s disease facts and figures","volume":"17","author":"Lane","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1902\/jop.2012.110676","article-title":"Advances in Surveillance of Periodontitis: The Centers for Disease Control and Prevention Periodontal Disease Surveillance Project","volume":"83","author":"Eke","year":"2012","journal-title":"J. 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