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.

项目四-总结