Decoding the Effects of Bexarotene treatment on brain of AD-like model mice: A Single-Cell Transcriptomic and Chromatin Accessibility Analysis [scRNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE283905 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Ligand activation of nuclear receptor has been linked with therapeutic implications in Alzheimer's Disease. In this study, we used AD mouse model treated with Bexarotene, an RXR agonist and performed scRNA-seq and snATAC-seq using the brain tissue. We reavealed changes in chromatin architure in brain of AD-lie mouse model in response to RXR ligand and link those changes to the initiation of transcriptional programs at a single-cell resolution.
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Project description:Ligand activation of nuclear receptor has been linked with therapeutic implications in Alzheimer's Disease. In this study, we used AD mouse model treated with Bexarotene, an RXR agonist and performed scRNA-seq and snATAC-seq using the brain tissue. We reavealed changes in chromatin architure in brain of AD-lie mouse model in response to RXR ligand and link those changes to the initiation of transcriptional programs at a single-cell resolution.
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Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.
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Project description:Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer’s disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3’-propyl-[1,1’-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRα over retinoic acid receptor (RARα) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects.
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Project description:Bexarotene is a specific RXR agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). The mechanism of action is pleiotropic but impacts directly on CTCL cell proliferation, chemotaxis and apoptosis, and indirectly on lymphoma immunity. Bexarotene causes hypothyroidism in more than 90% of patients thus requiring the concomitant administration of levothyroxine. Hereon we investigated the consequence of levothyroxine administration to the antineoplastic effect of bexarotene in CTCL. We found that bexarotene induces transcriptional and biological changes in CTCL cells related to decreased cell proliferation and chemotaxis, as well as increased proliferation and interferon response. Although lack of levothyroxine supplementation during bexarotene treatment increased apoptosis and decreased cell proliferation of CTCL cells in vitro and in vivo, it also decreased the lymphoma immunity. Since levothyroxine activates both the ubiquitous TRA nuclear receptor and the more restricted integrin V3 membrane receptor that is overexpressed in CTCL cells, we investigated their role in bexarotene treatment. We demonstrated that genetic and pharmacologic inhibition of the integrin V3 receptors resulted in improved bexarotene-induced effects on apoptosis, cell proliferation and chemotaxis while maintaining the lymphoma immunity. Our results provide a mechanistic rationale for evaluating the addition of the integrin V3 inhibitor cilengitide to CTCL therapeutic regimens that are based on bexarotene and levothyroxine supplementation.
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Project description:The efficiency of central nervous system (CNS) remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study we show that expression of genes involved in the retinoid X receptor (RXR) pathway are decreased with aging in myelin-phagocytosing cells. Loss of RXR function in young macrophages mimics aging by delaying remyelination after experimentally-induced demyelination, while RXR agonists partially restore myelin debris phagocytosis in aged macrophages. The FDA-approved RXR agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in aging human monocytes to a more youthful profile. These results reveal the RXR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics. 24 Human CD14+ monocyte-sorted PBMC samples representing 4 Healthy Volunteers (HV) and 4 Multiple Sclerosis (MS) patients under 3 different treatment conditions. Condition 1 = (-) Phagocystosis (-) Bexarotene. Condition 2 = (+) Phagocystosis (-) Bexarotene. Condition 3 = (+) Phagocystosis (+) Bexarotene.
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