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

项目总结/摘要 阿尔茨海默病（Alzheimer's Disease，AD）是一种以脑为主要表现的进行性神经退行性疾病 病理学、神经精神症状和认知衰退。一般来说，确认 AD的诊断还包括两种病理标志（如斑块和缠结 临床观察到的认知能力下降然而大多数AD患者 显示认知和临床表型，一部分个体具有提示 AD无相应的认知障碍。一种可能的解释是， “抵抗”的个体有补偿机制保护他们的认知状态， 病理学的存在。最近的工作从单核RNA测序后， 尸检的人类额叶皮质组织表明星形胶质细胞的分子上不同的亚群（a 脑中的非神经元细胞类型）在“抗性”与“非神经元细胞类型”中差异存在。 “易感”（因病理而认知下降）个体。然而，这一观察， 迄今为止，仅限于一个单一的大脑区域，在一个小样本，主要是白人 个体本提案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，以及它们与其他细胞类型的关联 大脑的多个区域都有异常通过一个单一的组合- 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的差异分布图， “抗性”和“易感”个体中的亚群，它们与病理学的空间关系 和其他细胞类型，以及参与星形胶质细胞介导的 对tau病理学的抗性。最终，描述特定的 星形胶质细胞亚群，它们之间的相互作用，以及参与耐药个体的途径 可以确定治疗途径，以减轻存在AD的认知下降 病理

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.