Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omics

项目 4：利用单细胞多组学对 APOE 基因型和 AD 病理学的细胞反应进行跨物种解析

• 批准号: 10271129
• 负责人: Michael Ryan Corces
• 金额: $ 96.57万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271129
• 关键词: ATAC-seq; Acute; Adverse effects; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Antisense Oligonucleotides; Behavioral; Brain; Brain region; Cell Communication; Cell Nucleus; Cells; Clinical; Cognition; Cognitive; Collaborations; Complex; Data; Disease; Dissection; Epilepsy; Etiology; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Goals; Hippocampus (Brain); Human; Impaired cognition; Inherited; Interneurons; Investigation; Lead; Link; Modeling; Molecular; Molecular Genetics; Molecular Target; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Parietal Lobe; Pathogenesis; Pathologic; Pathology; Phenotype; Prevention; Prevention strategy; Process; Proteins; Regulator Genes; Research; Sampling; Senile Plaques; Severities; Small Nuclear RNA; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Translating; Translations; apolipoprotein E-4; brain cell; cell type; cellular targeting; cohort; combinatorial; comorbidity; design; effective therapy; epigenomics; humanized mouse; mouse model; multiple omics; network dysfunction; neural network; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; optogenetics; response; single cell technology; tau Proteins; transcriptome sequencing; transcriptomics

PROJECT 4 – SUMMARY Alzheimer’s disease (AD) is driven by a complex, multifactorial etiology that has stymied progress toward effective therapies. Despite decades of research on amyloid-beta (Aβ) and tau, we do not fully understand the cellular and molecular effects of these key disease drivers. These pathologic proteins interact with genetic drivers, such as apolipoprotein E4 (APOE4), creating complex and diverse cellular and brain-regional effects. One promising approach to understanding the diverse effectors of AD pathogenesis is to study central processes that are perturbed by each disease driver. Both AD pathology and APOE genotype exacerbate neural network dysfunction in brain regions critical for cognition, nominating neural network function as one such critical central process. Besides causing AD-related cognitive decline, neural network dysfunction results in comorbidities such as subclinical epileptiform activity. The lack of a comprehensive picture of the cellular, molecular, and genetic underpinnings of AD underscores the need for detailed and rigorous dissection of the many factors that contribute to this disease. The goal of this PPG is to identify the cellular and molecular consequences of the interactions between Aβ, tau, and APOE and determine how they lead to prolonged neural network dysfunction. Genetic and pathologic alterations drive AD by affecting cellular state. For example, neuronal and glial cells interact with and are affected by Aβ and tau pathology, leading to changes in gene expression that are further altered by the genetic milieu of the cell, culminating in an altered cellular state. Understanding how cellular state changes and is controlled by multifactorial inputs of AD could lead to novel therapeutic strategies. However, these cellular responses are cell type– and cell context–specific. Techniques for single-cell transcriptomic and epigenomic profiling now make it possible to characterize the specific cellular response to combinatorial interactions between Aβ, tau, and APOE. To systematically understand cellular responses to Aβ, tau, and APOE in human AD, Project 4 will comprehensively characterize cell-type-specific transcriptomics and epigenomics in primary human samples. In Aim 1, we will perform single-nucleus (sn) transcriptomic and epigenomic profiling in human cohorts that have been rigorously characterized, both clinically and pathologically, and that vary in APOE genotype, Aβ and tau pathology, and cognitive state. In Aim 2, we will integrate these data with snRNA-seq results from novel humanized mouse lines designed to dissect the combinatorial effects of Aβ, tau, and APOE (with Projects 1–3). In Aim 3, we will use single-cell technologies to understand the effects of therapeutic reversal of prolonged neural network dysfunction in mouse models (with Projects 2 and 3). The results of the proposed studies, in concert with the other complementary projects, will provide an unparalleled characterization of the multifactorial etiology of neural network dysfunction in AD, and may suggest novel avenues for therapeutic intervention.

项目4 - 摘要 阿尔茨海默氏病（AD）是由复杂的多因素病因驱动的 有效的疗法。尽管数十年来研究了淀粉样蛋白β（Aβ）和tau，但我们并不完全了解 这些关键疾病驱动因素的细胞和分子作用。这些病理蛋白与遗传相互作用 驱动因素，例如载脂蛋白E4（APOE4），会产生复杂而多样的细胞和大脑区域作用。 理解AD发病机理潜水员影响的一种承诺方法是研究中心过程 每个疾病驱动器都会扰动。 AD病理学和APOE基因型加剧神经网络 大脑区域功能障碍对认知至关重要，提名神经网络作为这样的关键中心的功能 过程。除了引起与广告相关的认知下降外，神经网络功能障碍导致合并症此类 作为亚临床癫痫样活性。缺乏细胞，分子和遗传的全面图片 AD的基础强调了对促成许多因素的详细和严格解剖的需求 这种疾病。该PPG的目的是确定相互作用的细胞和分子后果 在Aβ，TAU和APOE之间，并确定它们如何导致延长神经网络功能障碍。 通过影响细胞状态，遗传和病理改变推动了AD。例如，神经元和神经胶质细胞 与Aβ和TAU病理相互作用并受到影响，导致基因表达变化 通过细胞的遗传环境改变，最终以改变的细胞状态。了解细胞状态 变化并由AD的多因素输入控制，可能会导致新的治疗策略。然而， 这些细胞反应是细胞类型和细胞环境特异性的。单细胞转录组和 现在的表观基因组分析使得表征对组合的特定细胞反应是可能的 Aβ，TAU和APOE之间的相互作用。系统地了解细胞对Aβ，TAU和APOE的反应 在人类广告中，项目4将全面地表征细胞型特异性转录组学和表观基因组学 主要人类样品。 在AIM 1中，我们将在人类同伙中执行单核（SN）转录组和表观基因组分析 在临床和病理上都严格表征，并且在APOE基因型，Aβ和 tau病理和认知状态。在AIM 2中，我们将将这些数据与新颖的SNRNA-SEQ集成 人源化的小鼠系旨在解剖Aβ，TAU和APOE的组合作用（具有1-3个项目）。 在AIM 3中，我们将使用单细胞技术来了解延长神经的热逆转的影响 鼠标模型中的网络功能障碍（带项目2和3）。拟议研究的结果，共同 随着其他完成项目，将提供多因素病因的无与伦比的表征 AD中的神经网络功能障碍的，并可能暗示了治疗干预的新途径。