APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice
APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice
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DOI：
10.1038/s41598-020-61142-8
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发表时间：
2020-03-09
影响因子：
4.6
通讯作者：
Nuriel, Tal
中科院分区：
文献类型：
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作者：
Area-Gomez, Estela;Larrea, Delfina;Nuriel, Tal
载脂蛋白E （APOE）的e4等位基因是迟发性阿尔茨海默病（AD）的主要遗传危险因素。然而，APOE4与AD之间关联的原因尚不清楚。虽然大部分研究都集中在apoE4蛋白增加A - ss聚集和减少A - ss清除的能力上，但也有大量数据表明apoE4对大脑中的许多其他过程产生负面影响，包括生物能量学。为了更全面地了解APOE4在AD发病机制中的作用，我们对APOE4和APOE3在老年APOE小鼠内嗅皮层（EC）和初级视觉皮层（PVC）中的表达进行了转录组学分析。该研究揭示了ec特异性氧化磷酸化相关基因（OxPhos）的上调。利用海马平台的后续分析显示，APOE4小鼠与APOE3小鼠相比，随着年龄的增长，海马和皮层的线粒体呼吸减少，但这些小鼠的EC没有。进一步的研究以及原始的转录组学数据表明，APOE4的表达在老年APOE小鼠EC中差异调节了多种生物能量通路，以提高该区域的线粒体偶联效率。考虑到EC作为人类AD病理影响的第一个区域的重要性，观察到EC对代谢应激源（如APOE4）的不同生物能量调节敏感，可能会指出AD发病机制中的一个致病因素。
The e4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of A ss, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4's role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.