Protein Signatures of APOE2 and Cognitive Aging

摘要 载脂蛋白E是一类参与脂代谢的蛋白质，其功能由 APOE基因的等位基因。该基因最不常见的等位基因，称为𝑒2，作为一种假定的 保护变种，当Schachter等人。注意到𝑒2在法语中出现的频率增加 百岁老人。从那时起，几项研究提供了证据，证明𝑒-2具有有益的神经保护作用 影响和促进长寿和健康衰老。新英格兰百岁老人研究(NECS)指导 自1994年以来，Perls博士已经招募了大约400名𝑒2携带者， 并与Barzilai博士领导的LonGenity研究(LS)和其他 百岁老人提出了强有力的证据，证明𝑒2可以延长寿命。尽管有多项研究 然而，与𝑒-2相关的生物学机制仍不清楚。我们生成了 与诺华公司合作，从226个NEC的血清中获得约5,000个蛋白质的蛋白质组数据集 参与者，年龄在50岁到115岁之间，被选中进行丰富 我们在𝑒基因分型的背景下分析了这些数据。在我们的分析中，我们 发现了一组与载脂蛋白E基因相关的蛋白质，并预测不同的 认知衰退的纵向模式。这些初步数据支持这样的假设： 有多种与载脂蛋白E基因相关的血浆蛋白(I)可用于预测 认知功能下降或保存得比APOE基因更好，以及(Ii)可以告诉我们 APOE的潜在作用机制，并提出预防或延迟的候选干预措施 神经退行性疾病和衰老中的认知衰退。我们建议在以下项目中检验这一假设 三种方式：我们将使用深入的蛋白质组学来验证、表征和扩展 50例不同载脂蛋白E基因携带者血浆中与载脂蛋白E基因相关的蛋白质。 这项分析可能会发现与载脂蛋白E基因相关的其他蛋白质生物标记物，如 以及可以改变其分子功能的翻译后修饰。到时候我们会的 600名受试者评价扩展蛋白质信号对衰老和认知功能减退的影响 百岁老人、他们的后代和来自NECS的对照组，并与LS复制发现。在一个 在这些受试者中，我们将检测几年来收集的第二份血液样本中的蛋白质水平 除了能够研究蛋白质特征的变化如何预测认知的变化 功能。我们还建议用选定的炎症和游离标记物来增强这些数据 脂肪酸是认知老化的重要因素，并对 在不同的目的中收集的数据旨在模拟将载脂蛋白E基因型别与 认知老化。总而言之，我们已经组建了一支称职的跨学科调查小组。 彻底评估和表征APOE基因类型的蛋白质特征 多用途的、有效的认知功能改变的生物标志物和可能的AD。这样做的结果 这项工作将提出决定载脂蛋白E𝑒2等位基因神经保护作用的可能机制。

Abstract Apolipoprotein E is a class of proteins involved in lipid metabolism with functions determined by alleles of the gene APOE. The least common allele of this gene, called 𝑒2, emerged as a putative protective variant when Schachter et al. noted an increased frequency of 𝑒2 in French centenarians. Since then several studies have provided evidence that 𝑒2 has a beneficial neuroprotective effect and promotes longevity and healthy aging. The New England Centenarian Study (NECS) directed by Dr. Perls has enrolled ~400 𝑒2 carriers since 1994, and in collaboration with the Longenity Study (LS) directed by Dr. Barzilai and other studies of centenarians produced strong evidence that 𝑒2promotes longevity. Despite multiple research efforts however the biological mechanisms associated with 𝑒2 are still unclear. We generated in collaboration with Novartis a proteomic dataset of ~5,000 proteins from sera of 226 NECS participants, ages 50 to 115 years, selected to be enriched of 𝑒2 and we analyzed these data in the context of APOE genotypes. In our analysis, we discovered a preliminary set of proteins that correlate with APOE genotypes and predict different longitudinal patterns of cognitive decline. These preliminary data support the hypothesis that there are multiple plasma proteins associated with APOE genotypes that (i) can be used to predict cognitive decline or preservation better than APOE genotypes, and (ii) can inform us about potential mechanisms of action of APOE and suggest candidate interventions to prevent or delay neurodegenerative diseases and cognitive decline in aging. We propose to test this hypothesis in three ways: we will use in-depth proteomics to validate, characterize and expand the set of proteins that correlate with APOE genotypes in plasma of 50 carriers of different APOE genotypes. This analysis will likely discover additional protein biomarkers associated with APOE genotypes as well as post- translational modifications that could modify their molecular functions. We will then evaluate the effect of the expanded protein signature on aging and cognitive decline in 600 centenarians, their offspring and controls from the NECS, and replicate findings with the LS. In a subset of these subjects, we will assay protein levels in a second blood sample collected few years apart to be able to examine how changes of the protein signature predict changes of cognitive functions. We also propose to augment these data with selected markers of inflammation and free fatty acids that are important factors in cognitive aging and conduct integrative analyses of the data collected in the various aims to model hypothetical mechanisms linking APOE genotypes to cognitive aging. In summary, we have assembled a competent, interdisciplinary team of investigators to thoroughly evaluate and characterize protein signatures of APOE genotypes that could become multipurpose, potent biomarkers of cognitive functions change and probable AD. The results of this work will suggest possible mechanisms that determine the neuroprotective effect of the APOE 𝑒2 allele.