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.

项目总结/文摘