Metabolomic/lipidomic analysis of apoE isoform effects in AD-linked brain regions

AD 相关大脑区域中 apoE 亚型效应的代谢组学/脂质组学分析

• 批准号: 9116739
• 负责人: Tal Nuriel
• 金额: $ 5.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116739
• 关键词: Abeta clearance; Adolescent; Affect; Alleles; Alzheimer' s Disease; Amyloid beta-Protein; Apolipoprotein E; Autopsy; Biochemical; Bioinformatics; Brain; Brain hemorrhage; Brain region; Caucasians; Cessation of life; Child; Computer software; Coupled; Data; Disease susceptibility; Emerging Technologies; Energy Metabolism Pathway; Genes; Health; Human; Imaging Techniques; Immunohistochemistry; Incidence; Individual; Lead; Lewy Body Dementia; Light; Link; Lipids; Mass Spectrum Analysis; Measures; Mediating; Metabolic Pathway; Methods; Mus; Neurologic; Neurons; Not Hispanic or Latino; Outcome; Parkinson' s Dementia; Pathogenesis; Pathology; Pathway interactions; Process; Protein Isoforms; Proteins; Regulation; Resistance; Risk; Role; Statistical Data Interpretation; Stroke; Structure; Techniques; Technology; Time; Tissues; Validation; Vertebral column; Western Blotting; age related; apolipoprotein E-3; apolipoprotein E-4; area striata; brain parenchyma; brain tissue; entorhinal cortex; genetic risk factor; male; mass spectrometer; metabolomics; novel; novel therapeutic intervention; novel therapeutics; prevent; research study; small molecule; theories; tool

DESCRIPTION (provided by applicant): Carriers of the apolipoprotein E (APOE) ε4 gene are at significantly increased risk for developing Alzheimer's disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear. The most widely accepted view is that the accelerated AD pathology observed in APOE ε4 carriers is due to a decreased ability of the apoE4 protein to clear Aβ from the brain. However, possession of the APOE ε4 gene also results in a number of other neurological deficits unrelated to Aβ clearance, including alterations in neuronal structure, thinner entorhinal cortex (EC) layers and poorer outcomes after stroke, suggesting that there may be other mechanisms involved in this process. In order to gain a more comprehensive understanding of the how the expression of different apoE isoforms affects the brain and how this may impact the risk of developing AD and other age-related neurological illnesses, we propose to use mass spectrometry to identify lipids and small-molecules whose levels are affected by changes in apoE isoform expression. To accomplish this, we will first extract lipids, small-molecules and proteins from pathology-free EC and primary visual cortex (PVC) tissues obtained from 14-month old mice and postmortem 19-55 year old individuals expressing differing apoE isoforms. The lipid and small-molecule fractions from these extracts will then be used to perform targeted lipidomics and untargeted metabolomics, followed by bioinformatic analysis and a variety of validation experiments, in order to determine the specific lipids, small-molecules and metabolic pathways that are affected by alternative apoE isoform expression in the brain. Thus far, preliminary studies have uncovered significant changes in energy metabolism pathways and several important lipid subclasses, demonstrating the power of these techniques for discovering previously unknown isoform-specific effects of apoE in the brain. We expect that the full study proposed herein will uncover further apoE isoform-specific changes in lipid and small-molecule levels and will lead to a greater understanding of how apoE4 influences AD pathology, potentially leading to new therapeutic strategies for AD and other neurological illnesses influenced by apoE4 expression.

描述(由申请人提供)：载脂蛋白E(ApoE)ε4基因携带者患阿尔茨海默病(AD)的风险显著增加。尽管已经提出了许多理论，但这种联系的原因仍然不清楚。最广泛接受的观点是，在载脂蛋白Eε4携带者中观察到的加速AD病理是由于载脂蛋白E4蛋白从脑中清除Aβ的能力降低。然而，拥有载脂蛋白Eε4基因也会导致其他一些与Aβ清除无关的神经缺陷，包括神经元结构改变，内嗅皮层(EC)层变薄，卒中后预后较差，这表明可能有其他机制参与了这一过程。为了更全面地了解不同载脂蛋白E亚型的表达如何影响大脑，以及这可能如何影响AD和其他与年龄相关的神经系统疾病的风险，我们建议使用质谱仪来识别其水平受载脂蛋白E亚型表达变化影响的脂质和小分子。为了做到这一点，我们将首先从14月龄小鼠和19-55岁死后表达不同载脂蛋白E亚型的小鼠和身体的初级视皮层(PVC)组织中提取脂类、小分子和蛋白质。然后，从这些提取物中提取的脂类和小分子部分将被用于进行靶向脂质组学和非靶向代谢组学，随后将进行生物信息学分析和各种验证实验，以确定特定的脂类、小分子和代谢途径受到大脑中替代载脂蛋白E亚型表达的影响。到目前为止，初步研究已经发现了能量代谢途径和几个重要的脂质亚类的显著变化，展示了这些技术在发现大脑中先前未知的载脂蛋白E异构体特异性效应方面的力量。我们预计，本文提出的全面研究将揭示载脂蛋白E亚型在脂质和小分子水平上的特异性变化，并将导致对载脂蛋白E4如何影响AD病理的更多了解，从而潜在地导致AD和其他受载脂蛋白E4表达影响的神经疾病的新治疗策略。