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According to the antiviral protection hypothesis, viral pathogens trigger aggregation of A\u03b2 peptides that are produced as a defense mechanism in response to infection to entrap and neutralize pathogens. To test the causative relationship between viral infection and A\u03b2 aggregation, the current study examined whether A\u03b2 plaques protect the mouse brain against Herpes Simplex Virus 1 (HSV\u20101) infection introduced via a physiological route and whether HSV\u20101 infection triggers formation of A\u03b2 plaques in a mouse model of late\u2010onset AD that does not develop A\u03b2 pathology spontaneously. In aged 5XFAD mice infected via eye scarification, high density of A\u03b2 aggregates did not improve survival time or rate when compared with wild type controls. In 5XFADs, viral replication sites were found in brain areas with a high density of extracellular A\u03b2 deposits, however, no association between HSV\u20101 and A\u03b2 aggregates could be found. To test whether HSV\u20101 triggers A\u03b2 aggregation in a mouse model that lacks spontaneous A\u03b2 pathology, 13\u2010month\u2010old hA\u03b2\/APOE4\/Trem2*R47H mice were infected with HSV\u20101 via eye scarification with the McKrae HSV\u20101 strain, intracranial inoculation with McKrae, intracranial inoculation after priming with LPS for 6\u2009weeks, or intracranial inoculation with high doses of McKrae or 17syn\u2009+\u2009strains that represent different degrees of neurovirulence. No signs of A\u03b2 aggregation were found in any of the experimental groups. Instead, extensive infiltration of peripheral leukocytes was observed during the acute stage of HSV\u20101 infection, and phagocytic activity of myeloid cells was identified as the primary defense mechanism against HSV\u20101. The current results argue against a direct causative relationship between HSV\u20101 infection and A\u03b2 pathology.<\/jats:p>","DOI":"10.1111\/bpa.13116","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T01:09:50Z","timestamp":1662426590000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A\u03b2 plaques do not protect against <scp>HSV<\/scp>\u20101 infection in a mouse model of familial Alzheimer's disease, and <scp>HSV<\/scp>\u20101 does not induce A\u03b2 pathology in a model of late onset Alzheimer's disease"],"prefix":"10.1111","volume":"33","author":[{"given":"Olga V.","family":"Bocharova","sequence":"first","affiliation":[{"name":"Center for Biomedical Engineering and Technology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Department of Anatomy and Neurobiology University of Maryland School of Medicine  Baltimore Maryland 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