{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:17:15Z","timestamp":1764260235460,"version":"build-2065373602"},"reference-count":113,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"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>The prevalence of Alzheimer\u2019s disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-\u03b2 (A\u03b2) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation\/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-\u03b1, IL-1\u03b2, MHC-II and C\/EBP-\u03b1 and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-\u03b1, IL-1\u03b2, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBP\u03b2 at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in A\u03b2 pathology and microglia\/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.<\/jats:p>","DOI":"10.3390\/cells11010137","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T22:51:50Z","timestamp":1641250310000},"page":"137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-9519","authenticated-orcid":false,"given":"Adelaide","family":"Fernandes","sequence":"first","affiliation":[{"name":"Central Nervous System, Blood and Peripheral Inflammation, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4994-7620","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Caldeira","sequence":"additional","affiliation":[{"name":"Neuroinflammation, Signaling and Neuroregeneration, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"given":"Carolina","family":"Cunha","sequence":"additional","affiliation":[{"name":"Neuroinflammation, Signaling and Neuroregeneration, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"},{"name":"Bruno Silva-Santos Lab, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1200-4602","authenticated-orcid":false,"given":"Elisabete","family":"Ferreiro","sequence":"additional","affiliation":[{"name":"MitoXT-Mitochondrial Toxicologu and Experimental Therapeutics Laboratory, CNC-Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-516 Coimbra, Portugal"},{"name":"III-Institute for Interdisciplinary Research (IIIUC), Universidade de Coimbra, 3004-516 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3418-3269","authenticated-orcid":false,"given":"Ana Rita","family":"Vaz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Medicines, Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"},{"name":"Neuroinflammation, Signaling and Neuroregeneration, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3024-9777","authenticated-orcid":false,"given":"Dora","family":"Brites","sequence":"additional","affiliation":[{"name":"Neuroinflammation, Signaling and Neuroregeneration, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,1]]},"reference":[{"key":"ref_1","first-page":"e12114","article-title":"Translational animal models for Alzheimer\u2019s disease: An Alzheimer\u2019s Association Business Consortium Think Tank","volume":"6","author":"Vitek","year":"2020","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00401-016-1662-x","article-title":"Alzheimer\u2019s disease: Experimental models and reality","volume":"133","author":"Drummond","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/alzrt269","article-title":"Alzheimer\u2019s disease drug-development pipeline: Few candidates, frequent failures","volume":"6","author":"Cummings","year":"2014","journal-title":"Alzheimer\u2019s Res. 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