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Although the primary target of influenza viruses is the lung, infection may manifest with acute and even chronic neurological complications (e.g., status epilepticus, encephalopathies, and encephalitis) potentially increasing the long-term risk for neurodegenerative diseases. We previously described that a peripheral influenza A virus (IAV) infection caused by non-neurotropic H3N2 (maHK68) variant leads to long-term neuroinflammation and synapse loss together with impaired memory formation in young adult mice. Processes of neuroinflammation have been associated with neurodegenerative diseases such as Alzheimer\u2019s disease (AD) and prolonged or excessive innate immune responses are considered a risk factor for AD. Here, the role of purely peripheral IAV infection for the development and progression of AD in a transgenic mouse model (APP\/PS1) was investigated. At 2 months of age, mice were infected with H3N2 IAV and the detailed analysis of microglia morphology revealed neuroinflammation in the hippocampus already of 6 months old non-infected APP\/PS1 mice together with impaired spatial learning, however, microglia activation, amyloid-\u03b2 plaques load and cognitive impairments were even more pronounced in APP\/PS1 mice upon H3N2 infection. Moreover, CA1 hippocampal dendritic spine density was reduced even at 120 dpi compared to wild-type and also to non-infected APP\/PS1 mice, whereas neuronal cells number was not altered. These findings demonstrate that non-neurotropic H3N2 IAV infection as a peripheral immune stimulation may exacerbate AD symptoms possibly by triggering microglial hyperactivation.<\/jats:p>","DOI":"10.3389\/fncel.2021.643650","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T01:01:21Z","timestamp":1619571681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":45,"title":["Long-Term Consequence of Non-neurotropic H3N2 Influenza A Virus Infection for the Progression of Alzheimer\u2019s Disease Symptoms"],"prefix":"10.3389","volume":"15","author":[{"given":"Shirin","family":"Hosseini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Michaelsen-Preusse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Schughart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Korte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/j.neuron.2019.12.031","article-title":"Human herpesvirus 6 detection in Alzheimer\u2019s disease cases and controls across multiple cohorts.","volume":"105","author":"Allnutt","year":"2020","journal-title":"Neuron"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2020.588872","article-title":"Cognitive and neuropsychiatric manifestations of COVID-19 and effects on elderly individuals with dementia.","volume":"12","author":"Alonso-Lana","year":"2020","journal-title":"Front. 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