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However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP\/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting A\u03b2-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell\u2013cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene\u2019s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD.<\/jats:p>","DOI":"10.3390\/ijms27052435","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T13:00:02Z","timestamp":1772802002000},"page":"2435","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain Single-Cell Transcriptional Responses to Bexarotene-Activated RXR in an Alzheimer\u2019s Disease Model"],"prefix":"10.3390","volume":"27","author":[{"given":"Carolina","family":"Saibro-Girardi","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Cell and Molecular Biology Graduate Program, Biotechnology Center, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8378-7459","authenticated-orcid":false,"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6938-6536","authenticated-orcid":false,"given":"Nicholas F.","family":"Fitz","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel P.","family":"Gelain","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Graduate Program, Biotechnology Center, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0249-0280","authenticated-orcid":false,"given":"Iliya","family":"Lefterov","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6761-0984","authenticated-orcid":false,"given":"Radosveta","family":"Koldamova","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. 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