APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
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DOI：
10.1186/s13195-019-0558-0
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发表时间：
2019-12-30
影响因子：
9
通讯作者：
Koldamova, Radosveta
中科院分区：
文献类型：
--
作者：
Lefterov, Iliya;Wolfe, Cody M.;Koldamova, Radosveta
背景先进的测序技术和改进的质谱学平台的应用揭示了阿尔茨海默病(AD)脑内基因表达和血脂的显著变化。到目前为止，这些结果已经促使人们使用“多组学”方法进行进一步的研究。考虑到apoE epsilon 4等位基因是AD的主要遗传危险因素，apoE epsilon 2等位基因的疾病保护作用，以及apoE在脑脂代谢中的主要作用，这些方法变得特别相关。方法采用APOE epsilon 2/c、apoE epsilon 3/3和apoE epsilon 4/c等位基因的顶下小叶标本，按年龄和性别配对，观察APOE等位基因转录本和脂体的变化。差异基因表达和共表达网络分析被用来识别上调和下调的基因本体论(GO)术语和与脂质组学数据相关的途径。结果根据APOE epsilon 2/c数据集与APOE epsilon 3/3和APOE epsilon 4/c脑标本的比较，确定了显著受影响的GO项和通路。对高度相关的网络模块中的基因列表和差异表达基因的分析表明，与细胞内蛋白质的蛋白酶体和溶酶体降解、蛋白质聚集体和细胞器、内质网胁迫、对未折叠蛋白质的反应以及线粒体功能、电子传递和ATP合成相关的基因在GO术语中显著丰富。与APOE epsilon 3/3和APOE epsilon 4/c相比，小核仁RNA编码单位对mRNA的转录后修饰非常重要，因此翻译和蛋白质合成在APOE epsilon 2/c脑样本中上调。脂质组学数据分析显示，10种主要脂类(APOE epsilon 4/c样本中唯一的减少)显著变化，最显著的是非双层形成磷脂酰乙醇胺和磷脂酸，以及线粒体膜形成脂类。结论尽管阿尔茨海默病已进入晚期，但死后脑转录本和脂质体的差异显著，提示载脂蛋白E等位基因在致病机制上存在差异。脂体和转录本内部和之间的相关性表明，蛋白酶体系统和自噬的变化-规范和选择性-协调作用，促进细胞内降解、蛋白质进入内质网、对内质网应激的响应、核仁修饰的mRNA，以及可能的APOE epsilon 2/c脑中的髓鞘形成。为了开发更有效的诊断方法和最终有效的治疗策略，需要进行更多的研究，并更好地了解阿尔茨海默病早期阶段蛋白平衡的分子机制。
Background The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer's disease (AD) brain. The results so far have prompted further research using "multi-omics" approaches. These approaches become particularly relevant, considering the inheritance of APOE epsilon 4 allele as a major genetic risk factor of AD, disease protective effect of APOE epsilon 2 allele, and a major role of APOE in brain lipid metabolism. Methods Postmortem brain samples from inferior parietal lobule genotyped as APOE epsilon 2/c (APOE epsilon 2/carriers), APOE epsilon 3/3, and APOE epsilon 4/c (APOE epsilon 4/carriers), age- and gender-matched, were used to reveal APOE allele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data. Results Significantly affected GO terms and pathways were determined based on the comparisons of APOE epsilon 2/c datasets to those of APOE epsilon 3/3 and APOE epsilon 4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated in APOE epsilon 2/c brain samples compared to both APOE epsilon 3/3 and APOE epsilon 4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOE epsilon 4/c samples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids. Conclusions The results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy-canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOE epsilon 2/c brains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.