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

TL;DR

This study explores how bexarotene, an RXR activator, affects brain cells in an Alzheimer’s disease model, revealing specific cellular responses and the role of APOE in these effects.

Contribution

The study identifies cell-type-specific transcriptional responses to bexarotene in Alzheimer’s disease models and highlights APOE-driven pathways as key mediators.

Findings

Bexarotene activates cholesterol biosynthesis and lipid metabolism in astrocytes and oligodendrocytes.

APOE expression is significantly elevated in microglia and oligodendrocytes.

Bexarotene modulates immune responses, promoting Aβ signatures while reducing inflammation in certain cells.

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.

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