Specific regional transcription of apolipoprotein E in human brain neurons.
Specific regional transcription of apolipoprotein E in human brain neurons.
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DOI：
10.1016/s0002-9440(10)65305-9
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发表时间：
1999-02
期刊：
影响因子：
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通讯作者：
P. Xu;J. Gilbert;Hui-Ling Qiu;J. Ervin;Tracie R. Rothrock-Christian;C. Hulette;D. Schmechel
中科院分区：
文献类型：
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作者：
P. Xu;J. Gilbert;Hui-Ling Qiu;J. Ervin;Tracie R. Rothrock-Christian;C. Hulette;D. Schmechel
在中枢神经系统损伤和疾病中，载脂蛋白E（APOE，基因；apoE，蛋白质）可能通过细胞外效应间接参与神经元损伤和死亡，和/或更直接地通过细胞内对神经元代谢的影响参与神经元损伤和死亡。虽然细胞内效应显然是由细胞外 apoE 的神经元摄取介导的，但最近在正常啮齿动物和人类 APOE 基因转基因小鼠损伤模型中进行的实验表明，神经元内合成的额外可能性。为了检查 APOE 是否可能由人类神经元合成，我们使用地高辛标记的反义和正义 cRNA 探针对三名非痴呆对照者和五名阿尔茨海默病 (AD) 患者的石蜡包埋和冷冻脑切片进行原位杂交。使用反义 APOE 探针，我们在神经胶质细胞中发现了预期的强杂交信号，并且在大脑皮层和海马的选定神经元中发现了通常较弱的信号。在海马中，在CA1至CA4区和齿状回的颗粒细胞层中观察到许多含有APOE mRNA的神经元。在这些区域中，可以在同一细胞类别的非杂交神经元附近观察到含有 APOE mRNA 的神经元。神经元中的 APOE mRNA 转录具有区域特异性。在小脑皮质中，APOE mRNA 仅在伯格曼胶质细胞和分散的星形胶质细胞中可见，但在浦肯野细胞或颗粒细胞神经元中没有。半相邻切片中的 ApoE 免疫细胞化学定位支持 APOE 转录的选择性。这些结果证明了APOE mRNA在人脑神经胶质细胞中转录和表达的预期结果。重要的新发现是，APOE mRNA也在额叶皮层和人类海马的许多神经元中转录和表达，但在同一大脑的小脑皮层神经元中却没有转录和表达。这种区域特异性的人类 APOE 基因表达表明，apoE 的合成可能在 AD 神经元的区域脆弱性中发挥作用。这些结果还为提出 apoE 同工型对神经元细胞骨架稳定性和代谢的作用的假设提供了直接的解剖学背景。
In central nervous system injury and disease, apolipoprotein E (APOE, gene; apoE, protein) might be involved in neuronal injury and death indirectly through extracellular effects and/or more directly through intracellular effects on neuronal metabolism. Although intracellular effects could clearly be mediated by neuronal uptake of extracellular apoE, recent experiments in injury models in normal rodents and in mice transgenic for the human APOE gene suggest the additional possibility of intraneuronal synthesis. To examine whether APOE might be synthesized by human neurons, we performed in situ hybridization on paraffin-embedded and frozen brain sections from three nondemented controls and five Alzheimer's disease (AD) patients using digoxigenin-labeled antisense and sense cRNA probes to human APOE. Using the antisense APOE probes, we found the expected strong hybridization signal in glial cells as well as a generally fainter signal in selected neurons in cerebral cortex and hippocampus. In hippocampus, many APOE mRNA-containing neurons were observed in sectors CA1 to CA4 and the granule cell layer of the dentate gyrus. In these regions, APOE mRNA containing neurons could be observed adjacent to nonhybridizing neurons of the same cell class. APOE mRNA transcription in neurons is regionally specific. In cerebellar cortex, APOE mRNA was seen only in Bergmann glial cells and scattered astrocytes but not in Purkinje cells or granule cell neurons. ApoE immunocytochemical localization in semi-adjacent sections supported the selectivity of APOE transcription. These results demonstrate the expected result that APOE mRNA is transcribed and expressed in glial cells in human brain. The important new finding is that APOE mRNA is also transcribed and expressed in many neurons in frontal cortex and human hippocampus but not in neurons of cerebellar cortex from the same brains. This regionally specific human APOE gene expression suggests that synthesis of apoE might play a role in regional vulnerability of neurons in AD. These results also provide a direct anatomical context for hypotheses proposing a role for apoE isoforms on neuronal cytoskeletal stability and metabolism.