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When a pathogen enters the body and reproduces, it can cause an infection, damage body cells, and cause illness symptoms that eventually lead to disease. Therefore, its prevention requires breaking the chain of infection.
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Basic Science and Pathogenesis.

Yi Lu1, Xuebao Wang1, Nicholas F Fitz1

  • 1University of Pittsburgh, Pittsburgh, PA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
PubMed
Summary

Bexarotene treatment in Alzheimer

Area of Science:

  • Neuroscience
  • Genomics
  • Epigenetics

Background:

  • Bexarotene, a Retinoid X Receptor (RXR) agonist, demonstrates neuroprotective potential in Alzheimer's disease (AD) models.
  • RXR activation influences key gene networks in neural development, neuroinflammation, and metabolism, crucial for brain function.
  • Understanding Bexarotene's impact on chromatin architecture and gene activity in AD is vital for therapeutic development.

Purpose of the Study:

  • To investigate the effects of Bexarotene on chromatin accessibility and gene expression in the brains of APP/PS1 AD mouse models.
  • To map transcriptomic and epigenomic alterations at single-cell resolution following Bexarotene treatment.
  • To identify cell-type-specific regulatory networks influenced by RXR activation in the AD brain.

Main Methods:

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  • Single-cell RNA sequencing (scRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) were performed on brain cells from Bexarotene-treated and vehicle-treated APP/PS1 mice.
  • Data integration using the ArchR pipeline identified cell populations, differentially accessible chromatin regions, and cell-type-specific transcription factors (TFs).
  • TF activity and regulatory networks were analyzed using TOBIAS, TF-COMB, and validated with ChIP-seq.

Main Results:

  • A comprehensive single-cell map revealed transcriptomic and epigenomic changes induced by Bexarotene in 37,640 cells and 61,353 nuclei.
  • Microglia and endothelial cells showed the most significant alterations, with changes in genes related to developmental functions.
  • Analysis identified RXR and heterodimer binding activity, elucidating transcriptional regulation mechanisms underlying Bexarotene's effects.

Conclusions:

  • Bexarotene modulates RXR-controlled gene networks in key brain cell types, including microglia and endothelial cells, in an AD model.
  • Integrated multi-omics data offer insights into how RXR activation may restore brain homeostasis by regulating neuroinflammation and amyloid pathology.
  • This study underscores the therapeutic potential of TF signaling pathways, particularly RXR activation, for Alzheimer's disease treatment.