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APOE Orchestrated Molecular Signatures in Aging Brain and AD-the Contribution of APOE2

APOE 在衰老大脑和 AD 中精心设计的分子特征——APOE2 的贡献

基本信息

批准号：
10450775
负责人：
RADOSVETA KOLDAMOVA
金额：
$ 63.59万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10450775
关键词：
ATP-Binding Cassette Transporters Acute Adrenal Glands Affect Affinity Aging Alleles Alzheimer&apos s Disease Amyloid beta-Protein Amyloid deposition Apolipoprotein E Astrocytes Autophagocytosis Autopsy Binding Biological Markers Biology Brain Cardiovascular Diseases Cell physiology Cholesterol Chromosome 19 Code Cognition Cognitive deficits Data Disease Early Diagnosis Epigenetic Process Exhibits Gene Cluster Gene Expression Gene Expression Profile Genes Genotype Goals High Density Lipoproteins Histones Homeostasis Human Human Pathology Hypolipoproteinemia Immunologic Receptors Impaired cognition Impairment Inflammation Injections Intervention Late Onset Alzheimer Disease Lipids Lipoproteins Low Density Lipoprotein Receptor Low-Density Lipoproteins Mammalian Cell Mediating Metabolic Microglia Mitochondria Molecular Molecular Profiling Molecular Target Mus Nerve Degeneration Network-based Neuroglia Neurons Pathogenesis Pathologic Patients Phagocytosis Phenotype Phospholipids Physiology Population Process Protein Isoforms Regulation Reporting Research Risk Role Sampling Signal Transduction Surface Technology Testing Tweens Very low density lipoprotein age effect age related aging brain apolipoprotein E-4 base brain cell cell type cognitive performance differential expression epigenome gene network genetic risk factor high risk immune function lipidome lipidomics mind control next generation sequencing novel therapeutic intervention particle prevent protective effect protein degradation receptor binding transcriptome transcriptomics uptake

项目摘要

The inheritance of APOEε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (LOAD). In fact, the inheritance of APOEε4 allele is the strongest known genetic risk factor in human pathology, but the mechanism is poorly understood. In contrast, APOEε2 allele is protective for AD and age-related diseases AD. While APOE has been associated with critical cellular functions such as oxidative processes, inﬂammation, glial cell and neuronal homeostasis, none of those can be dissociated from binding, transport and delivery of choles- terol and phospholipids to diﬀerent cell types by APOE containing lipoprotein particles. It is also uniformly ac- cepted that the above functions are APOE-isoform speciﬁc. Our preliminary data demonstrates that phospholipid composition of APOEε3/3 and APOEε4/4 AD brain differs significantly. Most prominent were changes in lipid classes that are critical in regulation of normal mitochondrial function and dynamics, but also in execution of metabolic cascades part of regulated intracellular protein degradation known as autophagy and mitophagy. We also found significant APOE isoform-specific differences between the transcriptomic profiles of the AD samples that substantiate molecular explanation of specific AD pathological changes in brain, based on perturbed gene expression. Our preliminary data also demonstrates that there is a significant difference in the phospholipid content of native APOE2, APOE3- and APOE4- lipoproteins suggesting that that they may affect differentially surface immune receptors and initiate different signal transduction cascades. We hypothesize that the APOE isoform-speciﬁc eﬀects on phenotype are driven by the diﬀerent phospholipid composition of APOE lipid particles and/or by the diﬀerential eﬀect of APOE isoforms on brain transcriptome and lipidome. In the First SA, we will establish the association of APOE alleles with AD brain transcriptome and lipidome and determine the allele specific impact on mitochondrial function and dynamics. We will use postmor- tem brain samples from AD patients and controls of different APOE genotypes to determine differences in tran- scriptomes and lipidomes within and between genotypes. We will generate and analyze correlated/co-expressed gene networks based on APOE allele associated differentially expressed genes and perform correlation analyses to identify associations between genes and lipids in brain. In the Second SA, we will investigate APOE isoform- dependent epigenetic and transcriptomic changes in AD brain and APOE Targeted Replacement mice. We will determine the enrichment of histone marks in specific cell types isolated from human AD and control brains and will examine APOE allele specific correlations to gene expression profiles. Next, we will examine the effect of aging on epigenome and transcriptome in distinct brain cell types of human APOE TR mice. In the Third SA, we will determine how APOE2 lipoproteins counteract the acute deleterious effects of A. The goals are to examine the effect of APOE2, E3 and E4 lipoproteins on: transcriptome of distinct brain cell populations and cognition in mice following intracranial injection of A

载脂蛋白Eε4等位基因的遗传是晚发性阿尔茨海默病(LOAD)最强的遗传危险因素。事实上，载脂蛋白Eε4等位基因的遗传是人类病理中已知的最强的遗传风险因素，但机制还不是很清楚。相反，载脂蛋白Eε2等位基因对AD和老年性疾病AD具有保护作用。虽然载脂蛋白E与氧化过程等关键细胞功能有关，但在ﬂ氨基酸中，胶质细胞细胞和神经元的动态平衡，这些都不能从胆碱的结合、运输和输送中分离出来。通过含脂蛋白颗粒的载脂蛋白对不同细胞类型的Terol和磷脂进行ﬀ分析。它也是统一的AC- 我们的初步数据表明，这些功能是apoe-ﬁc的异构体。载脂蛋白ε3/3和载脂蛋白ε4/4 AD脑的组成有显著差异。最突出的是血脂的变化。在正常线粒体功能和动力学的调节中至关重要的类，但在执行代谢级联作用是调节细胞内蛋白质降解的一部分，称为自噬和有丝分裂。我们还发现AD样本的转录图谱之间存在显著的APOE亚型特异性差异证实了基于扰动基因的脑内特定AD病理变化的分子解释表情。我们的初步数据也表明，在磷脂中有显著的差异天然载脂蛋白2、载脂蛋白3和载脂蛋白4的含量表明它们可能对表面免疫受体，并启动不同的信号转导级联。我们假设APOE异构体ﬁ对表型的影响是由不同的磷脂驱动的载脂蛋白脂质颗粒的组成和/或载脂蛋白亚型在脑转录组和/或脑转录组上的差异ﬀ等脂质体。在第一个SA中，我们将建立载脂蛋白E等位基因与AD脑转录组和并确定等位基因对线粒体功能和动力学的特异性影响。我们将使用邮局- 不同载脂蛋白E基因携带者与AD患者及对照组的脑组织标本比较基因内和基因间的手稿和脂体。我们将生成并分析相关/共同表达基于APOE等位基因相关差异表达基因的基因网络及其相关性分析以确定大脑中基因和血脂之间的联系。在第二个SA中，我们将研究APOE亚型- AD脑和APOE靶向替换小鼠的依赖表观遗传学和转录改变。我们会从人类AD和对照脑组织分离的特定细胞类型中确定组蛋白标记的富集度并将检查APOE等位基因与基因表达谱的特定相关性。接下来，我们将研究衰老对不同脑细胞类型的apoe-tr小鼠表观基因组和转录组的影响。在第三，SA，我们将确定载脂蛋白2脂蛋白如何抵消A的急性有害影响。目标是为了研究APOE2、E3和E4脂蛋白对不同脑细胞群体转录组的影响脑内注射对小鼠认知功能的影响