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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

APOEε4 等位基因的遗传是晚发性阿尔茨海默病 (LOAD) 最强的遗传风险因素。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风险因素，但机制尚不清楚。相比之下，APOEε2 等位基因对 AD 和年龄相关疾病 AD 具有保护作用。虽然 APOE 与氧化过程、炎症、神经胶质细胞等关键细胞功能相关。细胞和神经元的稳态，这些都不能与胆汁的结合、运输和递送分离。通过含有脂蛋白颗粒的 APOE 将特醇和磷脂作用于不同的细胞类型。它也是统一ac- 认为上述功能是 APOE 同种型特有的。我们的初步数据表明，磷脂 APOEε3/3 和 APOEε4/4 AD 大脑的组成存在显着差异。最显着的是血脂的变化对正常线粒体功能和动力学的调节至关重要的类别，而且对执行代谢级联是调节细胞内蛋白质降解的一部分，称为自噬和线粒体自噬。我们还发现 AD 样本的转录组谱之间存在显着的 APOE 同工型特异性差异基于扰动基因证实了大脑中特定 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会产生不同的影响表面免疫受体并启动不同的信号转导级联。我们假设 APOE 异构体对表型的特异性影响是由不同的磷脂驱动的 APOE 脂质颗粒的组成和/或 APOE 亚型对脑转录组的不同影响和脂质组。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，并脂质组并确定等位基因对线粒体功能和动力学的具体影响。我们将使用事后对 AD 患者和不同 APOE 基因型对照的大脑样本进行 TEM 分析，以确定转录组的差异基因型内和基因型之间的脚本组和脂质组。我们将生成并分析相关/共同表达基于APOE等位基因关联差异表达基因的基因网络并进行相关性分析确定大脑中基因和脂质之间的关联。在第二个 SA 中，我们将研究 APOE 亚型 - AD 大脑和 APOE 靶向替代小鼠中依赖的表观遗传和转录组变化。我们将确定从人类 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情况并将检查 APOE 等位基因与基因表达谱的特异性相关性。接下来，我们将检查衰老对人类 APOE TR 小鼠不同脑细胞类型的表观基因组和转录组的影响。在第三个 SA，我们将确定 APOE2 脂蛋白如何抵消 A 的急性有害作用。目标将检查 APOE2、E3 和 E4 脂蛋白对以下方面的影响：不同脑细胞群的转录组颅内注射 A 后小鼠的认知和认知能力