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 -概要 阿尔茨海默病（AD）是由一个复杂的，多因素的病因，阻碍了进展， 有效的治疗。尽管对淀粉样蛋白β（Aβ）和tau蛋白进行了数十年的研究，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效应。这些病理性蛋白质与遗传物质相互作用 驱动因素，如载脂蛋白E4（APOE 4），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物的一个有希望的方法是研究中枢过程 受到疾病驱动因素的影响。AD病理和APOE基因型均加重神经网络 功能障碍的大脑区域的关键认知，提名神经网络功能作为一个这样的关键中枢 过程除了引起AD相关的认知能力下降外，神经网络功能障碍还导致合并症， 亚临床癫痫样活动缺乏对细胞、分子和遗传的全面了解， AD的基础强调需要详细和严格的解剖的许多因素， 这种疾病。本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，神经元和神经胶质细胞 与Aβ和tau病理相互作用并受其影响，导致基因表达的变化， 由细胞的遗传环境改变，最终改变细胞状态。了解细胞状态 改变并受AD的多因素输入控制可能导致新的治疗策略。然而，在这方面， 这些细胞反应是细胞类型和细胞环境特异性的。单细胞转录组学和 表观基因组分析现在使得表征对组合免疫的特异性细胞应答成为可能。 Aβ、tau和APOE之间的相互作用。系统了解细胞对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， 主要人体样本 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， 在临床和病理上都有严格的特征，并且在APOE基因型、Aβ和 tau病理学和认知状态。在目标2中，我们将整合这些数据与snRNA-seq结果从新的 人源化小鼠系，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治疗性逆转延长的神经细胞凋亡的效果。 小鼠模型中的网络功能障碍（项目2和3）。拟议研究的结果， 与其他互补项目，将提供一个无与伦比的表征多因素病因学 神经网络功能障碍的AD，并可能提出新的途径，治疗干预。