Elucidating changes in astrocyte subpopulations associated with resistance to Alzheimers Disease pathology in multi-ethnic cohorts

阐明多种族群体中与阿尔茨海默病病理学抵抗相关的星形胶质细胞亚群的变化

• 批准号: 10162469
• 负责人: Vilas Menon
• 金额: $ 74.54万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10162469
• 关键词: Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Amyloid beta-Protein; Antibodies; Astrocytes; Autopsy; Brain; Brain Pathology; Brain region; Candidate Disease Gene; Caucasians; Cell Nucleus; Cells; Clinical; Cognitive; Data; Disease; Gene Expression; Genes; Goals; Human; Image; Immunohistochemistry; Impaired cognition; Indirect Immunofluorescence; Individual; Light; Maps; Mediating; Modality; Molecular; Molecular Computations; Molecular Profiling; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Proteins; Resistance; Resolution; Sampling; Spatial Distribution; Stains; Suggestion; System; Systems Biology; Therapeutic; Tissues; Work; aged; base; brain tissue; cell type; clinical phenotype; cohort; ethnic diversity; frontal lobe; gene interaction; genetic signature; genome-wide; multi-ethnic; neuropsychiatric symptom; response; tau Proteins; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract Alzheimer’s Disease (AD) is a progressive neurodegenerative disease, manifesting in brain pathology, neuropsychiatric symptoms, and cognitive decline. In general, confirmatory diagnosis of AD involves both pathological hallmarks (such as plaques and tangles) as well as clinically observed cognitive decline. Whereas most cases of patients with AD pathology show cognitive and clinical phenotypes, a subset of individuals have pathology suggestive of AD without the corresponding cognitive impairment. One possible explanation is that these “resistant” individuals have compensatory mechanisms protecting their cognitive status from the presence of pathology. Recent work from single-nucleus RNA-sequencing on post- mortem human frontal cortex tissue suggests molecularly distinct subsets of astrocytes (a non-neuronal cell type in the brain) are differentially present in “resistant” versus “susceptible” (cognitively declined with pathology) individuals. However, this observation so far has been limited to a single brain region in a small sample of primarily Caucasian individuals. This proposal aims to corroborate and extend this finding by investigating astrocyte subpopulations, their molecular profiles, and their associations with other cell types in multiple regions of the brain in an ethnically diverse. Through a combination of single- nucleus RNA-sequencing, spatial transcriptomics, immunohistochemistry, and systems biology, we propose to create a map of the differential distribution of astrocyte subpopulations in “resistant” and “susceptible” individuals, their spatial relation to pathology and other cell types, and candidate genes and pathways that involved in astrocyte-mediated resistance to tau pathology. Ultimately, characterizing the association between specific astrocyte subpopulations, their interactions, and pathways involved in resistant individuals may identify therapeutic avenues to mitigate cognitive decline in the presence of AD pathology.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，在大脑中表现出来 病理学，神经精神症状和认知能力下降。通常，确认 AD的诊断也涉及病理标志（例如斑块和缠结） 如临床观察到的认知能力下降。而大多数AD病理患者的病例 显示认知和临床表型，一部分个体具有病理学 AD没有相应的认知障碍。一种可能的解释是这些 “抵抗力”的个体具有保护其认知状况免受的补偿机制 病理的存在。单核RNA的最新工作 - Mortem人额皮层组织提出了分子不同的星形胶质细胞子集（a 大脑中的非神经元细胞类型）在“抗性”中与众不同 “敏感”（认知因病理学而下降）个体。但是，这个观察结果如此 在一小部分主要白种人样本中，远局限于单个大脑区域 个人。该建议旨在通过调查来证实和扩展这一发现 星形胶质细胞亚群，它们的分子谱及其与其他细胞类型的关联 在大脑的多个地区，在种族上多样化。通过单一组合 核RNA测序，空间转录组学，免疫组织化学和系统 生物学，我们建议创建星形胶质细胞差分分布的地图 在“抗性”和“敏感”个体中的亚群，它们与病理的空间关系 以及其他细胞类型，以及与星形胶质细胞介导的候选基因和途径 对tau病理的抗性。最终，表征特定之间的关联 星形胶质细胞亚群，它们的相互作用和抗性个体涉及的途径 可以识别出在AD存在下减轻认知能力下降的治疗途径 病理。