Protein Signatures of APOE2 and Cognitive Aging

摘要 载脂蛋白E是一类参与脂质代谢的蛋白质，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E102，作为一个假定的𝑒 当Schachter等人注意到法语中的p21 2频率增加时，𝑒 百岁老人从那时起，几项研究提供了证据，证明BMP2具有有益的神经保护作用。𝑒 影响和促进长寿和健康老龄化。新英格兰百岁老人研究（NECS） 自1994年以来，Perls博士已经招募了约400名携带者，𝑒 并与Barzilai博士指导的Longenity研究（LS）和其他研究合作， 百岁老人提出了强有力的证据，证明20岁可以促进长寿。𝑒尽管多项研究 然而，与BMP2相关的生物学机制仍不清楚。𝑒我们在 与诺华公司合作，从226名NECS患者血清中收集了约5，000种蛋白质的蛋白质组学数据集 年龄在50至115岁的参与者， 我们分析了APOE基因型背景下的这些数据。𝑒在分析中，我们 发现了一组与APOE基因型相关的初步蛋白质，并预测了不同的 认知衰退的纵向模式。这些初步的数据支持这样的假设， 有多种与APOE基因型相关的血浆蛋白，（i）可用于预测 认知功能下降或保存优于APOE基因型，（ii）可以告诉我们 APOE的潜在作用机制，并建议候选干预措施，以防止或延迟 神经退行性疾病和认知能力下降。我们建议在以下方面检验这一假设： 三种方法：我们将使用深入的蛋白质组学来验证，表征和扩展 50名不同APOE基因型携带者血浆中与APOE基因型相关的蛋白质。 这项分析可能会发现与APOE基因型相关的其他蛋白质生物标志物， 以及可以改变其分子功能的翻译后修饰。然后我们将 在600名受试者中评估扩展蛋白质签名对衰老和认知能力下降的影响， 百岁老人，他们的后代和控制从NECS，并复制与LS的结果。中 这些受试者的一个子集，我们将在几年内收集的第二份血液样本中检测蛋白质水平 除了能够检查蛋白质特征的变化如何预测认知功能的变化之外， 功能协调发展的我们还建议用选定的炎症标志物和游离的 脂肪酸是认知老化的重要因素，并对 在各种目的中收集的数据，以模拟将APOE基因型与 认知老化总之，我们已经组建了一个有能力的跨学科调查小组， 彻底评估和表征APOE基因型的蛋白特征， 认知功能改变和可能AD的多用途、有效生物标志物。的结果 这项工作将提出决定APOE β 2等位基因神经保护作用的可能机制。𝑒

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.