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期发作阿尔茨海默氏病（负载）的强遗传危险因素。实际上，ApoEε4等位基因的遗传是人类病理中已知的已知遗传风险因素，但是机制知之甚少。相比之下，APOEε2等位基因受AD和与年龄有关的疾病AD的保护。虽然APOE与关键细胞功能（例如氧化过程细胞和神经元体内稳态，这些都不能与choles的结合，运输和传递分离 - 含有含脂蛋白颗粒的APOE的Terol和磷脂对不同的细胞类型。它也是统一的表明上述功能是APOE-异型特定的。我们的初步数据表明磷脂 APOEε3/3和APOEε4/4 AD大脑的组成显着区别。最突出的是脂质的变化对于调节正常线粒体功能和动力学至关重要的类代谢级联反应的一部分受调节的细胞内蛋白质降解称为自噬和线粒体。我们还发现AD样品的转录组曲线之间存在明显的APOE同工型特异性差异这证实了基于扰动基因的特定AD病理变化的分子解释表达。我们的初步数据还表明，磷脂存在显着差异天然APOE2，APOE3-和APOE4-脂蛋白的含量表明它们可能影响不同表面免疫受体并启动不同的信号转导级联反应。我们假设APOE同工型特异性对表型的影响是由不同的磷脂驱动的 APOE脂质颗粒的组成和/或通过APOE同工型在脑转录组和脂肪组。在第一个SA中，我们将建立APOE等位基因与AD脑转录组和脂肪组并确定等位基因对线粒体功能和动力学的特异性影响。我们将使用邮政 - 来自AD患者的TEM脑样品和不同APOE基因型的对照，以确定转移的差异基因型内外的脚本组和脂质组。我们将生成和分析相关/共表达基于APOE等位基因的基因网络相关的基因不同并执行相关分析确定基因与脑中脂质之间的关联。在第二个SA中，我们将研究ApoE同工型 - AD脑和APOE靶向替代小鼠的依赖性表观遗传学和转录组变化。我们将确定从人AD和对照大脑分离的特定细胞类型中组蛋白标记的富集并将检查APOE等位基因与基因表达谱的特定相关性。接下来，我们将检查衰老对人ApoE TR小鼠不同脑细胞类型的表观基因组和转录组的影响。在第三SA，我们将确定APOE2脂蛋白如何抵消A的急性有害作用。目标正在检查APOE2，E3和E4脂蛋白对不同脑细胞群体的转录组的作用颅内注射后小鼠的认知