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: 10670350
• 负责人: Michael Ryan Corces
• 金额: $ 87.4万
• 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/10670350
• 关键词: ATAC-seq; Acceleration; Acute; Adverse effects; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Antisense Oligonucleotides; Apolipoproteins; Behavior assessment; Brain; Brain region; Cell Communication; Cell Nucleus; Cells; Clinical; Cognition; Cognitive; Collaborations; Complex; Data; Disease; Dissection; Etiology; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Goals; Hippocampus; Human; Impaired cognition; Inherited; Interneurons; Investigation; Lead; Link; Modeling; Molecular; 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; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Translating; Translations; apolipoprotein E-4; brain cell; cell type; cellular targeting; cognitive testing; cohort; combinatorial; comorbidity; data integration; design; effective therapy; epigenomic profiling; epigenomics; epileptiform; gene network; gene regulatory network; humanized mouse; mouse model; multiple omics; network dysfunction; neural network; neurotransmission; novel; novel therapeutic intervention; novel therapeutics; optogenetics; response; single cell technology; single nucleus RNA-sequencing; single-cell RNA sequencing; tau Proteins; transcriptome sequencing; transcriptomic profiling; 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 – 总结 阿尔茨海默氏病 (AD) 是由复杂的多因素病因引起的，该病因阻碍了该病的进展 有效的疗法。尽管对淀粉样蛋白 (Aβ) 和 tau 蛋白进行了数十年的研究，但我们尚未完全了解 这些关键疾病驱动因素的细胞和分子影响。这些病理蛋白与遗传相互作用 载脂蛋白 E4 (APOE4) 等驱动因素会产生复杂多样的细胞和大脑区域效应。 了解 AD 发病机制的多种效应子的一种有前景的方法是研究中心过程 受到每种疾病驱动因素的困扰。 AD 病理学和 APOE 基因型都会加剧神经网络 对认知至关重要的大脑区域功能障碍，将神经网络功能列为此类关键中枢功能之一 过程。除了导致 AD 相关的认知能力下降外，神经网络功能障碍还会导致合并症，例如 作为亚临床癫痫样活动。缺乏细胞、分子和遗传的全面了解 AD 的基础强调需要对促成 AD 的许多因素进行详细而严格的剖析 对这种疾病。该 PPG 的目标是确定相互作用的细胞和分子后果 Aβ、tau 和 APOE 之间的关系，并确定它们如何导致长期神经网络功能障碍。 遗传和病理改变通过影响细胞状态来驱动 AD。例如，神经元和神经胶质细胞 与 Aβ 和 tau 病理学相互作用并受其影响，导致基因表达发生进一步变化 受到细胞遗传环境的改变，最终导致细胞状态的改变。了解细胞状态 AD 的变化并受到多因素输入的控制，可能会导致新的治疗策略。然而， 这些细胞反应是特定于细胞类型和细胞环境的。单细胞转录组学技术 表观基因组分析现在可以表征对组合的特定细胞反应 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 AD 中，项目 4 将全面表征细胞类型特异性转录组学和表观基因组学 原始人类样本。 在目标 1 中，我们将在人类队列中进行单核 (sn) 转录组和表观基因组分析， 已在临床和病理学方面进行了严格的表征，并且 APOE 基因型、Aβ 和 tau 病理学和认知状态。在目标 2 中，我们将把这些数据与新颖的 snRNA-seq 结果整合起来。 人源化小鼠品系旨在剖析 Aβ、tau 和 APOE 的组合效应（项目 1-3）。 在目标 3 中，我们将使用单细胞技术来了解长期神经元治疗逆转的效果。 小鼠模型中的网络功能障碍（项目 2 和项目 3）。拟议研究的结果一致 与其他补充项目一起，将提供多因素病因学的无与伦比的表征 AD 中神经网络功能障碍的研究，可能会提出治疗干预的新途径。