Related Experiment Video
Updated: Mar 23, 2026
Visualizing Axonal Growth Cone Collapse and Early Amyloid β Effects in Cultured Mouse Neurons
Published on: October 30, 2018
RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Aβ oligomers
Kyong Nyon Nam1, Anais Mounier1, Nicholas F Fitz1
1Department of Environmental &Occupational Health, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
Abstract:
Bexarotene, a selective agonist for Retinoid X receptors (RXR) improves cognitive deficits and amyloid-β (Aβ) clearance in mice. Here we examine if the effect of bexarotene on RXR cistrome and transcriptomes depend on APOE isoform and Aβ deposition. We found bexarotene increased RXR binding to promoter regions in cortex of APOE3 mice. Rho family GTPases and Wnt signaling pathway were highly enriched in ChIP-seq and RNA-seq datasets and members of those pathways - Lrp1, Lrp5, Sfrp5 and Sema3f were validated. The effect of APOE isoform was compared in APOE3 and APOE4 mice and we found significant overlapping in affected pathways. ChIP-seq using mouse embryonic stem cells and enrichment levels of histone marks H3K4me3 and H3K27me3 revealed that, bexarotene induced epigenetic changes, consistent with increased neuronal differentiation and in correlation with changes in transcription. Comparison of transcriptome in APOE3 and APP/APOE3 mice revealed that amyloid deposition significantly affects the response to bexarotene. In primary neurons, bexarotene ameliorated the damaged dendrite complexity and loss of neurites caused by Aβ42. Finally, we show that the disruption of actin cytoskeleton induced by Aβ42 in vitro was inhibited by bexarotene treatment. Our results suggest a mechanism to establish RXR therapeutic targets with significance in neurodegeneration.
Insights
Bexarotene, a Retinoid X receptor (RXR) agonist, enhances cognitive function and amyloid clearance. Its effects on RXR targets depend on APOE, with potential for neurodegenerative disease therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Retinoid X receptors (RXRs) are crucial for neuronal function.
- Alzheimer's disease is characterized by amyloid-β (Aβ) plaques and cognitive decline.
- APOE genotype influences Alzheimer's risk and Aβ pathology.
Purpose of the Study:
- To investigate how bexarotene's effects on RXR signaling are influenced by APOE isoform and Aβ deposition.
- To elucidate the molecular mechanisms underlying bexarotene's therapeutic potential in neurodegeneration.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) to map RXR binding sites.
- RNA sequencing (RNA-seq) to analyze gene expression changes.
- In vitro studies using primary neurons and Aβ42 treatment.
Main Results:
- Bexarotene increased RXR binding and altered gene expression in APOE3 mice, enriching for Rho GTPases and Wnt signaling pathways.
- APOE isoform significantly impacted bexarotene's effects, yet overlapping pathways were observed between APOE3 and APOE4 models.
- Bexarotene mitigated Aβ42-induced neurite damage and actin cytoskeleton disruption in primary neurons, suggesting epigenetic modifications.
Conclusions:
- Bexarotene modulates RXR activity and downstream pathways, with its efficacy influenced by APOE genotype and Aβ presence.
- These findings highlight RXR as a therapeutic target for neurodegenerative diseases, offering a mechanism for bexarotene's neuroprotective effects.
