Apolipoprotein D Mediates Autocrine Protection of Astrocytes and Controls Their Reactivity Level, Contributing to the Functional Maintenance of Paraquat-Challenged Dopaminergic Systems
Apolipoprotein D Mediates Autocrine Protection of Astrocytes and Controls Their Reactivity Level, Contributing to the Functional Maintenance of Paraquat-Challenged Dopaminergic Systems
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DOI：
10.1002/glia.21200
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发表时间：
2011-10-01
期刊：
影响因子：
6.2
通讯作者：
Sanchez, Diego
中科院分区：
文献类型：
--
作者：
Bajo-Graneras, Raquel;Ganfornina, Maria D.;Sanchez, Diego
损伤和变性诱导的胶质细胞衍生因子的研究对于理解神经系统对恶化条件的反应是重要的。我们专注于载脂蛋白D（ApoD），一种由胶质细胞表达的脂质运载蛋白，在衰老、损伤或神经退行性变时强烈诱导。在这里，我们研究了野生型和ApoD-KO小鼠脑中的ApoD功能，结合星形胶质细胞培养的体内实验。在百草枯（PQ）处理的小鼠中测定了运动性能、多巴胺浓度和黑质中的基因表达水平。在星形胶质细胞培养物中检测ApoD转录的调节、氧化应激（OS）相关基因的分子筛选、细胞活力和氧化状态以及添加人ApoD的影响。我们证明：（1）ApoD是运动能力所必需的，它改变了PQ攻击的黑质纹状体系统的基因表达谱，并有助于其功能的维持：（2）ApoD在星形胶质细胞中的表达受OS反应性JNK通路的控制;（3）ApoD有助于星形胶质细胞的自分泌保护机制，避免过氧化脂质积累，改变参与ROS管理和OS炎症反应的基因的PQ转录反应;（4）向ApoD-KO星形胶质细胞添加人ApoD通过伴随蛋白质内化和调节星形胶质细胞反应性的机制促进存活。我们的数据支持ApoD有助于星形胶质细胞的耐力，并降低其在体外和体内的反应水平。ApoD作为星形胶质细胞的维持因子的功能将足以解释所观察到的保护ApoD的OS脆弱的多巴胺能电路在体内。(C)2011 Wiley-Liss，Inc.
The study of glial derived factors induced by injury and degeneration is important to understand the nervous system response to deteriorating conditions. We focus on Apolipoprotein D (ApoD), a Lipocalin expressed by glia and strongly induced upon aging, injury or neurodegeneration. Here we study ApoD function in the brain of wild type and ApoD-KO mice by combining in vivo experiments with astrocyte cultures. Locomotor performance, dopamine concentration, and gene expression levels in the substantia nigra were assayed in mice treated with paraquat (PQ). The regulation of ApoD transcription, a molecular screening of oxidative stress (OS)-related genes, cell viability and oxidation status, and the effects of adding human ApoD were tested in astrocyte cultures. We demonstrate that (1) ApoD is required for an adequate locomotor performance, modifies the gene expression profile of PQ-challenged nigrostriatal system, and contributes to its functional maintenance; (2) ApoD expression in astrocytes is controlled by the OS-responsive JNK pathway; (3) ApoD contributes to an autocrine protecting mechanism in astrocytes, avoiding peroxidated lipids accumulation and altering the PQ transcriptional response of genes involved in ROS managing and the inflammatory response to OS; (4) Addition of human ApoD to ApoD-KO astrocytes promotes survival through a mechanism accompanied by protein internalization and modulation of astroglial reactivity. Our data support that ApoD contributes to the endurance of astrocytes and decreases their reactivity level in vitro and in vivo. ApoD function as a maintenance factor for astrocytes would suffice to explain the observed protection by ApoD of OS-vulnerable dopaminergic circuits in vivo. (C) 2011 Wiley-Liss, Inc.