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: 10461846
• 负责人: Michael Ryan Corces
• 金额: $ 94.35万
• 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/10461846
• 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; 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; 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 阿尔茨海默病(AD)是由一种复杂的、多因素的病因驱动的，这种病因阻碍了 有效的治疗方法。尽管几十年来对淀粉样β蛋白(Aβ)和tau的研究，我们并不完全了解 这些关键疾病驱动因素的细胞和分子效应。这些病理蛋白与基因相互作用 驱动因素，如载脂蛋白E4(APOE4)，创造复杂和多样化的细胞和脑区域效应。 研究中枢过程是理解AD发病机制不同效应因素的一个有希望的途径 被每一位疾病驱动者所困扰。阿尔茨海默病病理和载脂蛋白E基因型均加重神经网络 大脑对认知至关重要的区域的功能障碍，将神经网络功能提名为这样一个关键的中枢 进程。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诸如 为亚临床癫痫样活动。缺乏对细胞、分子和基因的全面了解 AD的基础强调需要详细和严格地剖析促成因素的许多因素 对这种疾病。这个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的神经网络功能障碍。 遗传和病理改变通过影响细胞状态来驱动AD。例如，神经细胞和神经胶质细胞 与Aβ和tau病理相互作用并受其影响，导致基因表达的变化 被细胞的遗传环境改变，最终导致细胞状态改变。了解蜂窝状态如何 AD的改变和受多因素输入的控制可能导致新的治疗策略。然而， 这些细胞反应是特定于细胞类型和细胞环境的。单细胞转录和分离技术 表观基因组图谱现在使得表征特定的细胞对组合的反应成为可能 β、tau和apoE之间的相互作用。系统地了解细胞对β、tau和apoE的反应 在人类阿尔茨海默病中，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 主要的人体样本。 在目标1中，我们将在人类队列中执行单核(Sn)转录和表观基因组图谱 在临床和病理上都有严格的特征，而且在载脂蛋白E基因、Aβ和 Tau病理和认知状态。在目标2中，我们将把这些数据与来自NOVICE SNRNA-SEQ结果相结合 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延长的神经治疗逆转的效果。 小鼠模型中的网络功能障碍(项目2和3)。拟议研究的结果，一致 与其他补充项目一起，将提供无与伦比的多因素病因的表征 阿尔茨海默病的神经网络功能障碍的研究，并可能为治疗干预提供新的途径。