Characterize neuronal and glial cell-specific vulnerability to proteinopathies in Alzheimer's disease using multimodal single-nuclei genomic and epigenomic approaches

使用多模式单核基因组和表观基因组方法表征阿尔茨海默病中神经元和神经胶质细胞对蛋白质病的特异性脆弱性

• 批准号: 10666954
• 负责人: Borna Bonakdarpour
• 金额: $ 81.16万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666954
• 关键词: ATAC-seq; Acetylation; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; American; Amyloid beta-Protein; Animal Model; Astrocytes; Autopsy; Biological; Brain; Brain region; Cause of Death; Cell Nucleus; Cells; Cerebellum; Clinical; Clinical Data; Cognitive; Complex; Data; Data Analyses; Data Analytics; Dementia; Diflunisal; Disease; Disease Progression; Disease associated microglia; Drug Modulation; Drug Targeting; Drug usage; Freezing; Frontotemporal Dementia; Functional disorder; Funding; Genes; Genetic; Genomics; Heterogeneity; Hippocampus; Human; Individual; Inflammation; Investigation; Knowledge Portal; Laboratories; Link; Medicine; Microglia; Modeling; Molecular; Nature; Neocortex; Nerve Degeneration; Neuroglia; Neurons; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Population; Preclinical Testing; Process; Quantitative Trait Loci; Reproducibility; Research; Risk; Sampling; Severities; Systems Biology; Technology; Testing; Transgenic Mice; United States; Universities; Vulnerable Populations; abeta accumulation; biobank; brain cell; cell type; cohort; cost effective; drug development; drug repurposing; effective therapy; epigenome; epigenomics; ethnic diversity; functional genomics; gene regulatory network; genetic signature; genome sequencing; genome wide association study; genomic data; human data; human disease; induced pluripotent stem cell; inflammatory marker; intercellular communication; mouse model; multimodal data; multimodality; multiple omics; neocortical; neuropathology; novel; preclinical efficacy; protein TDP-43; resilience; risk variant; sex; sildenafil; single nucleus RNA-sequencing; stem cell model; tau Proteins; tau aggregation; tau-1; transcriptome; treatment response; whole genome

PROJECT SUMMARY Alzheimer’s disease (AD) is a devastating neurodegenerative condition that it is estimated to affect 16 million Americans by 2050. AD is mixed proteinopathies (e.g., amyloid-β (Aβ) aggregation, tau neurofibrillary tangles, and TDP-43 inclusions) and selectively affect certain regions of the brain (e.g., neocortex and hippocampus) with complex pathophysiology. and characterization of specific Although multiple studies have focused on genetic factors for AD, the delineation neuronal and glial cell populations with enriched vulnerability to proteinopathy in AD remains unknown. Our team has demonstrated that single-cell/nucleus multi-omics (snRNA-seq/snATAC- seq) can be used to investigate both “normal” and “pathological” neuronal and glial subpopulations from human post-mortem brains and we have also established a large human brain biobank with diverse proteinopathies (including Aβ, tau, TDP-43 and others). Moreover, we have demonstrated how targeting proteinopathy-specific networks, such as acetylated Tau and synergistic proteinopathy networks shared by Tau and Aβ, can identify repurposable treatments (e.g., sildenafil and diflunisal) for AD. Our preliminary snRNA-seq and snATACT-seq analyses of human post-mortem cerebellum regions from 7 individuals (n=4 [AD] and n=3 other dementia cases) have revealed unique neuronal and glial cell populations and genes/networks when comparing to traditional snRNA-seq data from neocortex and hippocampus. Our integrative snRNA-seq data analysis has also identified disease-relevant microglial subtypes, including microglia containing amyloid-b/phosphor-tau, as well as microglia enriched in expression of pro-inflammatory markers, using deep generative models. We therefore hypothesize that comprehensive characterization of human neuronal and glial cell genomic and epigenomic signatures and networks that are vulnerable to proteinopathies will help to identify novel mechanistic pathways and disease- modifying treatments. In Aim 1, we will generate comprehensive multi-ome data of human neuronal and glial cells vulnerable to AD proteinopathies. We will use a sample pooling snRNA-seq/snATAC-seq technology to analyze human post-mortem neocortex, hippocampus, and cerebellum with varying degrees of proteinopathy severity (amyloid-b, p-tau and TDP-43) and age-, sex- and APOE-matched cognitive healthy controls available from the Northwestern Alzheimer’s Disease Research Center. In Aim 2, we will test the hypothesis that neuronal and/or glial cell-specific genomic/epigenomic signatures and networks identify the molecular mechanism(s) of vulnerability and resilience in AD. These multimodal data analyses will integrate large snRNA-seq/snATAC-seq profiles with existing whole genome-sequencing data from the Alzheimer’s disease sequencing project (ADSP). In Aim 3, we will test the hypothesis that selective cellular vulnerability linked to genes/networks can be targeted via pharmacologic treatment to slow progression of AD-like disease in animal models. Successful completion of our project will identify new treatment opportunities that target specific neuronal and/or glial cell-specific risk/resilience genes and networks that confer vulnerability to proteinopathies in AD and other dementias.

项目概要 阿尔茨海默病 (AD) 是一种毁灭性的神经退行性疾病，估计影响 1600 万人 到 2050 年，美国人将出现 AD 是混合性蛋白质病（例如，β 淀粉样蛋白 (Aβ) 聚集、tau 神经原纤维缠结、 和 TDP-43 内含物）并选择性地影响大脑的某些区域（例如新皮质和海马体） 具有复杂的病理生理学。 和具体的表征 尽管多项研究都集中在 AD 的遗传因素上，但对 AD 的描述 神经元和神经胶质细胞群对蛋白质病具有丰富的脆弱性 AD 仍然未知。我们的团队已经证明单细胞/核多组学 (snRNA-seq/snATAC- seq）可用于研究人类的“正常”和“病理”神经元和神经胶质亚群 死后大脑，我们还建立了一个包含多种蛋白质病变的大型人脑生物库 （包括 Aβ、tau、TDP-43 等）。此外，我们还演示了如何针对特定蛋白病。 网络，例如乙酰化 Tau 以及 Tau 和 Aβ 共享的协同蛋白病网络，可以识别 AD 的可重复治疗（例如西地那非和二氟尼柳）。我们的初步 snRNA-seq 和 snATACT-seq。 对 7 名个体的死后小脑区域进行分析（n=4 [AD] 和 n=3 其他痴呆病例） 与传统的相比，揭示了独特的神经和神经胶质细胞群和基因/网络 我们的综合 snRNA-seq 数据分析还确定了来自新皮质和海马体的 snRNA-seq 数据。 与疾病相关的小胶质细胞亚型，包括含有淀粉样蛋白-b/磷-tau的小胶质细胞，以及小胶质细胞 使用深度生成模型丰富了促炎标记物的表达。 人类神经和神经胶质细胞基因组和表观基因组特征的综合表征 易受蛋白质病影响的网络将有助于识别新的机制途径和疾病 在目标 1 中，我们将生成人类神经和神经胶质的综合多组数据。 我们将使用样本池 snRNA-seq/snATAC-seq 技术来检测易受 AD 蛋白病影响的细胞。 分析具有不同程度蛋白质病的人类死后新皮质、海马体和小脑 提供严重程度（淀粉样蛋白-b、p-tau 和 TDP-43）以及年龄、性别和 APOE 匹配的认知健康对照 来自西北阿尔茨海默病研究中心的研究人员在目标 2 中，我们将检验神经元的假设。 和/或神经胶质细胞特异性基因组/表观基因组特征和网络识别的分子机制 这些多模式数据分析将整合大型 snRNA-seq/snATAC-seq。 使用来自阿尔茨海默病测序项目 (ADSP) 的现有全基因组测序数据进行分析。 在目标 3 中，我们将测试以下假设：可以针对与基因/网络相关的选择性细胞脆弱性 通过药物治疗来减缓动物模型中 AD 样疾病的进展。 我们的项目将确定针对特定神经和/或神经胶质细胞特异性的新治疗机会 导致 AD 和其他痴呆症中蛋白质病易感性的风险/弹性基因和网络。