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.

项目摘要 阿尔茨海默氏病（AD）是一种破坏性的神经退行性疾病，据估计会影响1600万 到2050年，美国人是混合的蛋白质病（例如，淀粉样蛋白β（Aβ）聚集，tau神经原纤维缠结， 和TDP-43包含物），并有选择地影响大脑的某些区域（例如，新皮层和海马） 具有复杂的病理生理学。 和特定的表征 尽管多项研究集中于AD的遗传因素，但描述 神经元和神经胶质细胞群体具有丰富的蛋白质病的脆弱性 广告仍然未知。我们的团队已经证明了单细胞/核Multi-omics（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 验尸大脑，我们还建立了一个具有潜水蛋白质的大型人脑生物库 （包括Aβ，TAU，TDP-43等）。此外，我们已经证明了如何靶向蛋白质病特异性 网络，例如Tau和Aβ共享的乙酰化tau和协同蛋白质病网络，可以识别 AD的可重新处理治疗（例如西地那非和Diflunisal）。我们的初步snrna-seq和snatact-seq 从7个个体（n = 4 [ad]和n = 3个其他痴呆症病例）对人类后小脑区域的分析 与传统相比，已经揭示了独特的神经元和神经胶质细胞群以及基因/网络 来自新皮层和海马的SnRNA-Seq数据。我们集成的SNRNA-seq数据分析也已确定 与疾病相关的小胶质细胞亚型，包括含有淀粉样蛋白-B/磷酸的小胶质细胞，以及小胶质细胞 使用深化通用模型丰富了促炎标记的表达。因此，我们假设 人类神经元和神经胶质细胞基因组和表观基因组特征以及 容易患蛋白质病的网络将有助于确定新型的机械途径和疾病 - 修改治疗。在AIM 1中，我们将生成人类神经和神经胶质的综合性数据 细胞容易受到AD蛋白质病的影响。我们将使用样本池snRNA-seq/snatac-seq技术 分析人类验尸新皮层，海马和小脑，具有不同程度的蛋白质病 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氏病研究中心。在AIM 2中，我们将测试神经元的假设 和/或神经胶质细胞特异性基因组/表观基因组信号和网络识别分子机制 广告中的脆弱性和韧性。这些多模式数据分析将整合大型SNRNA-SEQ/SNATAC-SEQ 具有来自阿尔茨海默氏病测序项目（ADSP）的现有全基因组测序数据的概况。 在AIM 3中，我们将检验以下假设：可以针对与基因/网络相关的选择性细胞漏洞 通过药物治疗，在动物模型中慢慢进展AD样疾病。成功完成 我们的项目将确定针对特定神经元和/或神经胶质细胞特异性的新治疗机会 风险/弹性基因和网络会使AD和其他痴呆症中蛋白质病的脆弱性。