Mounier Anais, Georgiev Danko, Nam Kyong Nyon, Fitz Nicholas F, Castranio Emilie L, Wolfe Cody M, Cronican Andrea A, Schug Jonathan, Lefterov Iliya, Koldamova Radosveta
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and.
Institute for Diabetes, Obesity and Metabolism and Functional Genomics Core, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
J Neurosci. 2015 Aug 26;35(34):11862-76. doi: 10.1523/JNEUROSCI.1001-15.2015.
Bexarotene-activated retinoid X receptors (RXRs) ameliorate memory deficits in Alzheimer's disease mouse models, including mice expressing human apolipoprotein E (APOE) isoforms. The goal of this study was to gain further insight into molecular mechanisms whereby ligand-activated RXR can affect or restore cognitive functions. We used an unbiased approach to discover genome-wide changes in RXR cistrome (ChIP-Seq) and gene expression profile (RNA-Seq) in response to bexarotene in the cortex of APOE4 mice. Functional categories enriched in both datasets revealed that bexarotene-liganded RXR affected signaling pathways associated with neurogenesis and neuron projection development. To further validate the significance of RXR for these functions, we used mouse embryonic stem (ES) cells, primary neurons, and APOE3 and APOE4 mice treated with bexarotene. In vitro data from ES cells confirmed that bexarotene-activated RXR affected neuronal development at different levels, including proliferation of neural progenitors and neuronal differentiation, and stimulated neurite outgrowth. This effect was validated in vivo by demonstrating an increased number of neuronal progenitors after bexarotene treatment in the dentate gyrus of APOE3 and APOE4 mice. In primary neurons, bexarotene enhanced the dendritic complexity characterized by increased branching, intersections, and bifurcations. This effect was confirmed by in vivo studies demonstrating that bexarotene significantly improved the compromised dendritic structure in the hippocampus of APOE4 mice. We conclude that bexarotene-activated RXRs promote genetic programs involved in the neurogenesis and development of neuronal projections and these results have significance for the improvement of cognitive deficits.
Bexarotene-activated retinoid X receptors (RXRs) ameliorate memory deficits in Alzheimer's disease mouse models, including mice expressing human apolipoprotein E (APOE) isoforms. The goal of this study was to gain further insight into molecular mechanisms whereby ligand-activated RXR can affect or restore cognitive functions. We used an unbiased approach to discover genome-wide changes in RXR cistrome (ChIP-Seq) and gene expression profile (RNA-Seq) in response to bexarotene in the cortex of APOE4 mice. Functional categories enriched in both datasets revealed that liganded RXR affected signaling pathways associated with neurogenesis and neuron projection development. The significance of RXR for these functions was validated in mouse embryonic stem cells, primary neurons, and APOE3 and APOE4 mice treated with bexarotene.
贝沙罗汀激活的视黄酸X受体（RXRs）可改善阿尔茨海默病小鼠模型中的记忆缺陷，包括表达人类载脂蛋白E（APOE）异构体的小鼠。本研究的目的是进一步深入了解配体激活的RXR影响或恢复认知功能的分子机制。我们采用无偏倚方法，发现APOE4小鼠皮质中响应贝沙罗汀的RXR顺式作用组（ChIP-Seq）和基因表达谱（RNA-Seq）的全基因组变化。两个数据集中富集的功能类别显示，贝沙罗汀配体化的RXR影响与神经发生和神经元投射发育相关的信号通路。为了进一步验证RXR对这些功能的重要性，我们使用了小鼠胚胎干细胞、原代神经元以及用贝沙罗汀处理的APOE3和APOE4小鼠。来自胚胎干细胞的体外数据证实，贝沙罗汀激活的RXR在不同水平上影响神经元发育，包括神经祖细胞的增殖和神经元分化，并刺激神经突生长。通过证明贝沙罗汀处理后APOE3和APOE4小鼠齿状回中神经祖细胞数量增加，在体内验证了这一效应。在原代神经元中，贝沙罗汀增强了以分支、交叉和分叉增加为特征的树突复杂性。体内研究证实了这一效应，表明贝沙罗汀显著改善了APOE4小鼠海马体中受损的树突结构。我们得出结论，贝沙罗汀激活的RXR促进参与神经发生和神经元投射发育的遗传程序，这些结果对改善认知缺陷具有重要意义。
贝沙罗汀激活的视黄酸X受体（RXRs）可改善阿尔茨海默病小鼠模型中的记忆缺陷，包括表达人类载脂蛋白E（APOE）异构体的小鼠。本研究的目的是进一步深入了解配体激活的RXR影响或恢复认知功能的分子机制。我们采用无偏倚方法，发现APOE4小鼠皮质中响应贝沙罗汀的RXR顺式作用组（ChIP-Seq）和基因表达谱（RNA-Seq）的全基因组变化。两个数据集中富集的功能类别显示，配体化的RXR影响与神经发生和神经元投射发育相关的信号通路。RXR对这些功能的重要性在小鼠胚胎干细胞、原代神经元以及用贝沙罗汀处理的APOE3和APOE4小鼠中得到验证。
