Protein Signatures of APOE2 and Cognitive Aging

APOE2 的蛋白质特征和认知衰老

• 批准号: 10451539
• 负责人: THOMAS T PERLS
• 金额: $ 45.56万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451539
• 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 基因APOE的等位基因。 当Schachter等人没有增加法语的频率时，保护性变体 一百六岁的人。 效果并促进长寿和健康老化。 自1994年以来，Perls博士已招募了约400架载体 并与Barzilai博士指导的纵向研究（LS）和其他研究 百岁老人提供了有力的证据，表明𝑒2促进了长寿。 但是，与𝑒2相关的生物学机制仍不清楚 与Novartis合作一个蛋白质组学数据集，该数据集由226个NEC的血清中约5,000种蛋白质合作 50至115岁的参与者被选为丰富 𝑒2，我们在APOE基因型的背景下分析了数据。 发现了一组与基因型相关的蛋白质集并预测不同的 认知能力下降的纵向模式。 与APOE基因型相关的多个血浆蛋白（i）可用于预测 与APOE基因型相比，认知能力下降或保存更好，（ii）可以告知我们 APOE的潜在机制，并建议候选候选糖果intints预防或延迟 神经退行性疾病和衰老的认知下降。 三种方式：我们将使用深入的蛋白质组学来验证，表征和展开 与50个不同APOE基因型的50个载体的血浆中APOE基因型相关的蛋白质。 这种分析可能会发现与APOE基因型相关的其他蛋白质生物标志物作为 以及可以修改其分子功能的翻译后修饰 评估600的蛋白质签名蛋白签名的认知下降 百岁老人，他们的后代和NEC的控制，并在ls中复制发现 这些受试者的子集，我们将在第二个血液样本中分析蛋白质水平几年 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。 脂肪酸是认知衰老和进行IND进行IND进行综合分析的重要因素 在各种目的中收集的数据，旨在建模将APOE基因型连接到的假设机制 认知衰老。 彻底评估和表征APOE基因型的蛋白质特征 多功能，有效的认知功能的生物标志物会改变和可能的AD。 工作wirl提出了可能的机制APOE2等位基因的神经保护作用。