Astrocytic CCAAT/Enhancer Binding Protein δ Regulates Neuronal Viability and Spatial Learning Ability via miR-135a.
Astrocytic CCAAT/Enhancer Binding Protein δ Regulates Neuronal Viability and Spatial Learning Ability via miR-135a.
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DOI：
10.1007/s12035-015-9359-z
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发表时间：
2016-08
影响因子：
5.1
通讯作者：
Wang JM
中科院分区：
文献类型：
--
作者：
Chu YY;Ko CY;Wang WJ;Wang SM;Gean PW;Kuo YM;Wang JM
阿尔茨海默病（AD）的进展与星形胶质细胞诱导的神经炎症有关。然而，星形胶质细胞与学习障碍和AD中神经元丢失相关的详细机制尚不清楚。在这里，我们提供了新的证据，星形胶质细胞miR-135 a是至关重要的神经元活力和空间学习能力在体内。与APPswe/PS1/E9双基因（AppTg）小鼠相比，AppTg/Cebpd-/-小鼠表现出空间学习改善。miR-135 a是一种CCAAT/增强子结合蛋白δ（CEBPD）应答性miRNA，可通过其3′非翻译区（3′UTR）抑制血小板反应蛋白1（THBS 1）/Thbs 1（小鼠）的转录。我们使用不同的实验方法来减弱星形胶质细胞中CEBPD/Cebpd（小鼠）或miR-135 a的表达，并发现以下结果：THBS 1/Thbs 1表达增加，神经元凋亡减少，神经突生长增加。重要的是，发现向AppTg小鼠脑中注射miR-135 a拮抗剂（AM 135 a）可防止神经元凋亡并改善空间学习能力。总之，我们的研究结果证明了星形胶质细胞CEBPD的关键功能，并指出miR-135 a拮抗剂作为治疗阿尔茨海默病的有吸引力的治疗靶点。本文的在线版本（doi：10.1007/s12035-015-9359-z）包含补充材料，可供授权用户使用。
The progression of Alzheimer’s disease (AD) has been associated with astrocytes-induced neuroinflammation. However, the detailed mechanism of astrocytes associated with learning impairments and neuronal loss in AD is poorly defined. Here, we provide novel evidences that astrocytic miR-135a is critical for neuronal viability and spatial learning ability in vivo. The AppTg/Cebpd −/− mice showed a spatial learning improvement compared with the APPswe/PS1/E9 bigenic (AppTg) mice. miR-135a was found to be a CCAAT/enhancer binding protein δ (CEBPD) responsive miRNA and can repress the transcription of thrombospondin 1 (THBS1) / Thbs1 (mouse) via its 3′-untranslated region (3′UTR). We used different experimental approaches to attenuate the expression of CEBPD/Cebpd (mouse) or miR-135a in astrocytes and found the following results: increase in THBS1/Thbs1 expression, decrease in neuronal apoptosis, and increase in growth of neurites. Importantly, injection of miR-135a antagonist (AM135a) into the brain of AppTg mice was found to prevent neuronal apoptosis and improved the spatial learning ability. Together, our findings demonstrate a critical function for the astrocytic CEBPD, and point to miR-135a antagonist as an attractive therapeutic target for the treatment of Alzheimer’s disease. The online version of this article (doi:10.1007/s12035-015-9359-z) contains supplementary material, which is available to authorized users.