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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：
10170188
负责人：
RADOSVETA KOLDAMOVA
金额：
$ 63.28万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170188
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 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

APOEε4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，APOEε4等位基因的遗传是人类病理学中已知最强的遗传危险因素，但机制知之甚少。而APOEε2等位基因对AD及年龄相关疾病具有保护作用。虽然APOE与重要的细胞功能如氧化过程有关，但在再生、神经胶质细胞和神经元的稳态，没有一个可以与结合，运输和交付的胆- 胆固醇和磷脂通过含有脂蛋白颗粒的APOE与不同的细胞类型结合。它也是一致的AC- 认为上述功能是APOE亚型特异性的。我们的初步数据表明磷脂 APOEε3/3和APOEε4/4在AD脑中的组成有显著差异。最突出的是脂质的变化类是至关重要的正常线粒体功能和动力学的调节，但也在执行代谢级联部分调节细胞内蛋白质降解，称为自噬和线粒体自噬。我们还发现AD样本的转录组学特征之间存在显著的APOE亚型特异性差异这证实了基于干扰基因AD脑中特定病理变化的分子解释表情我们的初步数据还表明，在磷脂中存在显著差异，天然APOE 2、APOE 3-和APOE 4-脂蛋白的含量表明，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亚型对表型的特异性影响是由不同的磷脂通过APOE脂质颗粒的组合物和/或通过APOE同种型在脑转录组上的差异表达，脂质体。在第一个SA中，我们将建立APOE等位基因与AD脑转录组的关联，脂质组和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postmor- 从AD患者和不同APOE基因型的对照者中提取脑组织样本，以确定在AD患者和对照者中，基因型内和基因型之间的脚本体和脂质体。我们将生成和分析相关/共表达的基于APOE等位基因相关差异表达基因的基因网络，并进行相关性分析以确定基因和大脑中脂质之间的关联。在第二个SA中，我们将研究APOE亚型- AD脑和APOE靶向替代小鼠中的依赖性表观遗传和转录组学变化。我们将确定从人AD和对照大脑中分离的特定细胞类型中组蛋白标记的富集并将检查APOE等位基因特异性与基因表达谱的相关性。接下来，我们将研究衰老对人APOE TR小鼠不同脑细胞类型表观基因组和转录组的影响。在第三，我们将确定APOE 2脂蛋白如何抵消A β的急性有害作用。的目标研究APOE 2、E3和E4脂蛋白对不同脑细胞群转录组的影响脑内注射阿托伐他汀对小鼠认知功能的影响