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Interestingly, growing evidence supports the role of herpes simplex virus type 1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1 infection could promote the spread of phosphorylated tau (ptau) among neurons via EV. We analyzed the ptau species that were secreted via EV following HSV-1 infection in neuroblastoma cells and primary neurons, focusing particularly on T205, T181, and T217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressing human tau tagged with GFP (htau\n              <jats:sup>GFP<\/jats:sup>\n              ), we found that recipient tau knockout (KO) neurons uptook EV that are loaded with HSV-1-induced phtau\n              <jats:sup>GFP<\/jats:sup>\n              . Finally, we exploited an\n              <jats:italic>in vivo<\/jats:italic>\n              model of acute infection and assessed that cerebral HSV-1 infection promotes the release of ptau via EV in the brain of infected mice. Overall, our data suggest that, following HSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Herpes simplex virus type 1 (HSV-1) infection that reaches the brain has been repeatedly linked with the appearance of the pathognomonic markers of Alzheimer\u2019s disease (AD), including accumulation of amyloid beta and hyperphosphorylated tau proteins, and cognitive deficits. AD is a multifactorial neurodegenerative disease representing the most common form of dementia in the elderly, and no cure is currently available, thus prompting additional investigation on potential risk factors and pathological mechanisms. Here, we demonstrate that the virus exploits the extracellular vesicles (EV) to disseminate phosphorylated tau (ptau) among brain cells. Importantly, we provide evidence that the HSV-1-induced EV-bearing ptau can be undertaken by recipient neurons, thus likely contributing to misfolding and aggregation of native tau, as reported for other AD models. Hence, our data highlight a novel mechanism exploited by HSV-1 to propagate tau-related damage in the brain.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01522-24","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T13:01:53Z","timestamp":1724763713000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":25,"title":["HSV-1 infection induces phosphorylated tau propagation among neurons via extracellular vesicles"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1723-405X","authenticated-orcid":false,"given":"V.","family":"Protto","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9558-3047","authenticated-orcid":false,"given":"M. T.","family":"Miteva","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, CNR, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-4662","authenticated-orcid":false,"given":"F.","family":"Iannuzzi","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, CNR, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4751-4263","authenticated-orcid":false,"given":"M. E.","family":"Marcocci","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6729-6967","authenticated-orcid":false,"given":"D. D.","family":"Li Puma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4215-1643","authenticated-orcid":false,"given":"R.","family":"Piacentini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-6206","authenticated-orcid":false,"given":"M.","family":"Belli","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy"},{"name":"Laboratory of Molecular, Cellular and Ultrastructural Pathology, IRCCS San Raffaele Roma, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3150-6461","authenticated-orcid":false,"given":"L.","family":"Sansone","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy"},{"name":"Laboratory of Molecular, Cellular and Ultrastructural Pathology, IRCCS San Raffaele Roma, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1121-4464","authenticated-orcid":false,"given":"A.","family":"Pietrantoni","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-1685","authenticated-orcid":false,"given":"C.","family":"Grassi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. 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