Protein Signatures of APOE2 and Cognitive Aging

APOE2 的蛋白质特征和认知衰老

• 批准号: 10219143
• 负责人: THOMAS T PERLS
• 金额: $ 64.14万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219143
• 关键词: Age; Aging; Alleles; Alzheimer' s Disease; Apolipoprotein E; Biological; Biological Assay; Biological Markers; Blood specimen; Boston; Cardiovascular system; Centenarian; Cognitive aging; Collaborations; Data; Data Analyses; Data Set; Dementia; Disease; Early Diagnosis; Enrollment; Ethnic Origin; Evaluation; Event; Frequencies; Funding; Genes; Genotype; Human; Impaired cognition; Inflammation; Intervention; Late Onset Alzheimer Disease; Link; Longevity; Measures; Modeling; Molecular; Monitor; Neurodegenerative Disorders; New England; Nonesterified Fatty Acids; Participant; Pattern; Plasma; Plasma Proteins; Post-Translational Protein Processing; Prevalence; Proteins; Proteomics; Public Health; Research; Research Personnel; Risk Factors; Role; SNP genotyping; Sampling; Set protein; Structure; Subjects Selections; Technology; Testing; Therapeutic; Translating; United States National Institutes of Health; Universities; Validation; Work; aging population; cognitive change; cognitive function; cohort; cost; early detection biomarkers; healthy aging; inflammatory marker; insight; lipid metabolism; offspring; predictive signature; preservation; prevent; protective allele; protein biomarkers; rate of change; screening; socioeconomics; therapeutic target

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.

抽象的 载脂蛋白 E 是一类参与脂质代谢的蛋白质，其功能由以下因素决定： APOE 基因的等位基因。该基因最不常见的等位基因称为 𝑒2，作为假定的等位基因出现 Schachter 等人时的保护性变体。注意到法语中𝑒2 的频率增加 百岁老人。从那时起，多项研究提供的证据表明𝑒2 具有有益的神经保护作用 效果并促进长寿和健康老龄化。新英格兰百岁老人研究 (NECS) 指导 自 1994 年以来，Perls 博士已招募了约 400 名𝑒2 携带者， 并与 Barzilai 博士指导的长寿研究 (LS) 以及其他研究合作 百岁老人提供了强有力的证据证明𝑒2可以延长寿命。尽管进行了多项研究 然而，与𝑒2相关的生物学机制仍不清楚。我们生成于 与诺华 (Novartis) 合作提供了来自 226 个 NECS 血清的约 5,000 种蛋白质的蛋白质组数据集 参与者，年龄 50 至 115 岁，经过挑选以丰富内容 𝑒2，我们在 APOE 基因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 APOE 基因型相关并预测不同的蛋白质 认知能力下降的纵向模式。这些初步数据支持以下假设： 有多种与 APOE 基因型相关的血浆蛋白 (i) 可用于预测 与 APOE 基因型相比，认知能力下降或保存更好，并且 (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预防或延迟 神经退行性疾病和衰老认知能力下降。我们建议在 三种方式：我们将使用深入的蛋白质组学来验证、表征和扩展一组 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。 该分析可能会发现与 APOE 基因型相关的其他蛋白质生物标志物，例如 以及可以改变其分子功能的翻译后修饰。我们随后将 评估扩展的蛋白质特征对 600 名患者的衰老和认知能力下降的影响 百岁老人、他们的后代和来自 NECS 的对照，并通过 LS 复制研究结果。在一个 对于这些受试者的子集，我们将检测几年收集的第二份血液样本中的蛋白质水平 除了能够检查蛋白质特征的变化如何预测认知的变化 功能。我们还建议用选定的炎症标记物和游离标记物来增强这些数据。 脂肪酸是认知衰老的重要因素，并对这些脂肪酸进行综合分析 各种目的收集的数据旨在模拟将 APOE 基因型与 认知老化。总之，我们组建了一支有能力的跨学科研究团队 彻底评估和表征 APOE 基因型的蛋白质特征，这些特征可能成为 认知功能变化和可能的 AD 的多用途、有效的生物标志物。这样做的结果 这项工作将提出确定 APOE 𝑒2 等位基因神经保护作用的可能机制。