Topographic, cell type and molecular pathway characterization ofAlzheimer's disease using single cell transcriptomics and epigenomics

使用单细胞转录组学和表观基因组学对阿尔茨海默病进行地形、细胞类型和分子途径表征

• 批准号: 10112803
• 负责人: Ed Lein
• 金额: $ 451.05万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112803
• 关键词: Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amyloid beta-Protein; Antibodies; Appearance; Autopsy; Biology; Brain; Brain region; Cell Nucleus; Cells; Chromatin; Clinical; Cognition; Communities; Conflict (Psychology); Data; Data Set; Databases; Dementia; Disease; Disease Progression; Epigenetic Process; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Gliosis; Goals; Immunoglobulin Variable Region; Individual; Link; Maps; Measurement; Memory; Methods; Methylation; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Nuclear; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Phase; Phenotype; Population; Process; Protocols documentation; RNA; Regulator Genes; Resistance; Resolution; Resources; Sampling; Senile Plaques; Severities; Severity of illness; Sorting - Cell Movement; Specificity; Staging; Standardization; Stereotyping; Structure; Surveys; Techniques; Time; Tissues; amyloid pathology; base; brain tissue; cell type; cohort; comorbidity; cost; design; disease diagnosis; disease phenotype; disorder subtype; drug discovery; epigenomics; extracellular; follow-up; hyperphosphorylated tau; insight; misfolded protein; multiple omics; neuron loss; neuropathology; next generation; normal aging; progressive neurodegeneration; success; tau Proteins; tau aggregation; transcriptome sequencing; transcriptomics

ABSTRACT (PROJECT 2) Alzheimer's disease (AD) is a highly penetrant neurodegenerative disease projected to affect 13.8 million cases in the US by 2050 at a cost of $1.1 trillion if no treatment is developed. AD is characterized by stereotyped progressive neurodegeneration and accumulation of two misfolded proteins in brain regions important for cognition and memory. Neurofibrillary tangles (NFTs) of hyperphosphorylated tau follow a progression like neurodegeneration, while extracellular amyloid beta (Aβ) plaques are initially detected in cortical and deep brain structures. It is unclear whether these pathologies are causal or effects of other underlying processes and currently no anti-tau or anti- Aβ therapies stop or reverse AD. Gene expression studies of AD have largely been performed on tissue or cell populations, and impact of neuronal loss and gliosis on these results is unknown. Epigenetic modifications are also associated with AD, though methylation studies have produced conflicting results and no clear pattern of epigenetic dysregulation associated directly with AD progression has emerged. The present study adapts recently developed high-throughput, single-cell methods for transcriptomic and epigenetic analysis to the identify molecular and gene regulatory hallmarks of “clinically typical” AD without significant co-morbidities. Building off a detailed understanding of neurotypical adult cell types, the project aims to identify transcriptional changes in specific cell types or classes correlated with increasing severity of AD pathology in different brain regions affected by the disease, and then identify gene and chromatin accessibility changes with pathology in vulnerable cell populations. This project will initially optimize single nucleus RNA-seq and epigenetics methods for use with postmortem samples of varying pathology and tissue quality, and generate reference datasets for brain regions to be analyzed in AD. Low-cost, droplet-based single nucleus RNA-seq will then be used to classify and characterize cell types in regions differentially affected by tau and amyloid pathology from many donors spanning AD progression with quantified tau and Aβ pathologies. A broader set of brain regions will then be surveyed on a subset of cases with consistent AD-related phenotypes to understand whether there is a common AD signature across brain regions, and whether signatures of AD can be detected prior to the emergence of neuropathology. Finally, higher-resolution methods will target transcriptomic and epigenetic changes in AD associated with pathology and disease diagnosis in specific cell types, aimed at achieving a mechanistic understanding of AD phenotypes. Using this design, this project can directly probe dysregulated gene networks within affected cell types for the first time, providing a potential causal link between genetic or epigenetic states and resulting gene expression. The resulting datasets and platform will produce valuable insights into the cellular and molecular basis of AD and will be made publicly accessible through the Data Core.

摘要（项目2） 阿尔茨海默氏病（AD）是一种高度渗透性神经退行性疾病，预计会影响1380万 到2050年，美国的案件为1.1万亿美元，如果未开发治疗。广告以刻板印象为特征 对大脑区域中两种错误折叠蛋白的进行性神经变性和积累 认知和记忆。高磷酸化tau的神经原纤维缠结（NFTS）遵循类似的进展 神经变性，而细胞外淀粉样β（Aβ）斑块最初在皮质和深脑中检测到 结构。目前尚不清楚这些病理是因果关系还是其他基本过程的影响 目前尚无抗TAU或抗Aβ疗法停止或反向AD。 AD的基因表达研究在很大程度上已经 在组织或细胞群体上进行，神经元丧失和神经胶质的影响对这些结果的影响尚不清楚。 表观遗传修饰也与AD相关，尽管甲基化研究导致了冲突 结果且没有直接与AD进程相关的表观遗传失调的明确模式出现。 本研究改编了最近开发了用于转录组和的高通量单细胞方法 表观遗传学分析，鉴定“临床上典型” AD的分子和基因调节标志 显着的合并症。该项目的目的是建立对神经型成人细胞类型的详细了解 识别特定细胞类型或类的转录变化与AD严重程度的增加相关 受该疾病影响的不同大脑区域的病理，然后识别基因和染色质的可及性 脆弱细胞群体中的病理变化。该项目最初将优化单核RNA-seq 和表观遗传学方法，用于与病理和组织质量不同的事后样本使用，并产生 在AD中分析的大脑区域的参考数据集。低成本的基于液滴的单核RNA-seq将 然后用于对受TAU和淀粉样病理影响不同的区域中的细胞类型进行分类和表征 来自跨越AD进展的许多供体，具有定量的TAU和Aβ病理。更广泛的大脑 然后，将对具有一致的与广告相关表型的病例的一部分进行调查，以了解是否了解是否存在 大脑区域都有一个共同的AD签名，以及是否可以检测到AD的签名 神经病理学的出现。最后，高分辨率方法将靶向转录组和表观遗传学 特定细胞类型中与病理和疾病诊断相关的AD的变化，旨在实现 对AD表型的机械理解。使用此设计，该项目可以直接探测失调 第一次受影响细胞类型中的基因网络，提供遗传或之间的潜在因果关系 表观遗传态和产生的基因表达。由此产生的数据集和平台将产生价值 对AD的细胞和分子基础的见解，并将通过数据核心公开访问。