| First Author | Lefterov I | Year | 2015 |
| Journal | Neurobiol Dis | Volume | 82 |
| Pages | 132-140 | PubMed ID | 26071899 |
| Mgi Jnum | J:284615 | Mgi Id | MGI:6141086 |
| Doi | 10.1016/j.nbd.2015.05.019 | Citation | Lefterov I, et al. (2015) RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment. Neurobiol Dis 82:132-140 |
| abstractText | We have recently demonstrated that short term bexarotene treatment of APP/PS1 mice significantly improves their cognitive performance. While there were no changes in plaque load, or insoluble Abeta levels in brain, biochemical analysis strongly suggested improved clearance of soluble Abeta, including Abeta oligomers. To get further insight into molecular mechanisms underlying this therapeutic effect, we explored genome-wide differential gene expression in brain of bexarotene and control treated APP/PS1 mice. We performed high throughput massively parallel sequencing on mRNA libraries generated from cortices of bexarotene or vehicle treated APP/PS1 mice and compared the expression profiles for differential gene expression. Gene Ontology (GO) Biological Process categories with the highest fold enrichment and lowest False Discovery Rate (FDR) are clustered in GO terms immune response, inflammatory response, oxidation-reduction and immunoglobulin mediated immune response. Chromatin immunoprecipitation (ChIP) followed by ChIP-QPCR, and RT-QPCR expression assays were used to validate select genes, including Trem2, Tyrobp, Apoe and Ttr, differentially expressed in response to Retinoid X Receptor (RXR) activation. We found that bexarotene significantly increased the phagocytosis of soluble and insoluble Abeta in BV2 cells. The results of our study demonstrate that in AD model mice expressing human APP, gene networks up-regulated in response to RXR activation by the specific, small molecule, ligand bexarotene may influence diverse regulatory pathways that are considered critical for cognitive performance, inflammatory response and Abeta clearance, and may provide an explanation of the bexarotene therapeutic effect at the molecular level. This study also confirms that unbiased massive parallel sequencing approaches are useful and highly informative for revealing brain molecular and cellular mechanisms underlying responses to activated nuclear hormone receptors in AD animal models. |
