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ABCA7 transports lipids from\/across cell membranes, regulates A\u03b2 peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We developed the first humanized, Cre-inducible <jats:italic>ABCA7<\/jats:italic>\n              <jats:sup>\n                <jats:italic>flx<\/jats:italic>\n              <\/jats:sup> knock-in mouse model, crossbred it with the APPPS1-21 \u03b2-amyloidosis model, and generated constitutive ABCA7<jats:sup>ko<\/jats:sup> and microglia <jats:italic>Cx3cr1<\/jats:italic>-specific conditional ABCA7<jats:sup>ko<\/jats:sup> AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Constitutive knockout of the <jats:italic>Abca7<\/jats:italic> gene in APPPS1 mice increased the levels of A\u03b242 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1\u03b2 and TNF\u03b1. Interestingly, microglia-specific ABCA7<jats:sup>ko<\/jats:sup> restored A\u03b2<jats:sub>42<\/jats:sub> peptide levels and IBA1<jats:sup>+<\/jats:sup> and GFAP<jats:sup>+<\/jats:sup> and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7<jats:sup>ko<\/jats:sup> microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13195-025-01673-2","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T15:51:38Z","timestamp":1737993098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer\u2019s disease mice"],"prefix":"10.1186","volume":"17","author":[{"given":"Irene","family":"Santos-Garc\u00eda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Bascu\u00f1ana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Brackhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Villa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Eiriz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Br\u00fcning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Pahnke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"1673_CR1","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1002\/alz.12068","volume":"16","author":"AA Report","year":"2020","unstructured":"Report AA. 2020 Alzheimer\u2019s disease facts and figures. 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