Brain Single-Cell Transcriptional Responses to Bexarotene-Activated RXR in an Alzheimer's Disease Model.

Overview

1. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA or (C.S.-G.); (Y.L.)
2. Cell and Molecular Biology Graduate Program, Biotechnology Center, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, RS, Brazil

Abstract

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. 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 Aβ-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–cell 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’s 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE283905, at NCBI GEO; found in “Data Availability Statement”

Other data links

• ncbi.nlm.nih.gov/geo, NCBI; found in “Data Availability Statement”

Data Availability Statement

Raw data single-cell RNA-seq are publicly available at GEO (https://www.ncbi.nlm.nih.gov/geo/ (accessed on 20 February 2026), GEO accession: GSE283905 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE283905)). This paper does not report the original code. Any additional information required to reanalyze the data reported in this paper is available from the corresponding author upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 6 keywords, 18 MeSH terms, 4 funders, 94 references.

Cite

This paper

Saibro-Girardi, C., Lu, Y., Fitz, N. F., Gelain, D. P., Lefterov, I., & Koldamova, R. (2026). Brain Single-Cell Transcriptional Responses to Bexarotene-Activated RXR in an Alzheimer's Disease Model. International journal of molecular sciences, 27(5), 2435. https://doi.org/10.3390/ijms27052435

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