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Flow cytometry based, <jats:italic>in-vivo<\/jats:italic> A\u03b2 uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04<jats:sup>+<\/jats:sup> fibrillar A\u03b2. Lastly, we use Y-maze testing to analyze the effects of <jats:italic>Cx3cr1<\/jats:italic> deficiency on working memory.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Disease progression in 5xFAD;<jats:italic>Cx3cr1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial A\u03b2 phagocytosis and lysosomal acidification in 5xFAD;<jats:italic>Cx3cr1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice is impaired <jats:italic>in-vivo<\/jats:italic>. Interestingly, <jats:italic>Cx3cr1<\/jats:italic> deficiency results in heighted accumulation of neurotoxic, oligomeric A\u03b2, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6\u00a0month-old mice indicate dysregulated TGF\u03b2-signaling and heightened ROS metabolism in 5xFAD;<jats:italic>Cx3cr1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Lastly, microglia in 6\u00a0month-old 5xFAD;<jats:italic>Cx3cr1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice express a \u2018degenerative\u2019 phenotype characterized by increased levels of <jats:italic>Ccl2<\/jats:italic>, <jats:italic>Ccl5<\/jats:italic>, <jats:italic>Il-1\u03b2<\/jats:italic>, <jats:italic>Pten<\/jats:italic> and <jats:italic>Cybb<\/jats:italic> along with reduced <jats:italic>Tnf<\/jats:italic>, <jats:italic>Il-6<\/jats:italic> and <jats:italic>Tgf\u03b21<\/jats:italic> mRNA.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p><jats:italic>Cx3cr1<\/jats:italic> deficiency impairs microglial uptake and degradation of fibrillar A\u03b2, thereby triggering increased accumulation of neurotoxic A\u03b2 species. Furthermore, loss of <jats:italic>Cx3cr1<\/jats:italic> results in microglial dysfunction typified by dampened TGF\u03b2-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that A\u03b2-driven microglial dysfunction in <jats:italic>Cx3cr1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13024-022-00545-9","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T12:03:13Z","timestamp":1656417793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":114,"title":["CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"17","author":[{"given":"Shweta S.","family":"Puntambekar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Moutinho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Bor-Chian","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Jadhav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danika","family":"Tumbleson-Brink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananya","family":"Balaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin Alvarado","family":"Benito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guixiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Oblak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian A.","family":"Lasagna-Reeves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary E.","family":"Landreth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce T.","family":"Lamb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"545_CR1","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1111\/jnc.13632","volume":"139","author":"E Karran","year":"2016","unstructured":"Karran E, de Strooper B. 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