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

项目摘要/摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病，表现为脑部 病理学、神经精神症状和认知功能减退。一般来说，验证性的 AD的诊断还包括两个病理特征(如斑块和缠结) 正如临床观察到的认知能力下降一样。而大多数AD患者的病理情况 表现出认知和临床表型，部分个体有病理提示 AD患者没有相应的认知障碍。一种可能的解释是，这些 “抵抗力”个体具有补偿机制，保护他们的认知状态不受 病理学的存在。单核RNA测序的最新工作 人额叶皮质死亡组织提示星形胶质细胞的分子亚群(a 脑组织中的非神经细胞类型)的区别在于 “易感”(认知功能减退并伴有病态)的个体。然而，这种观察结果是这样的 FAR仅限于以高加索人为主的小样本中的单个大脑区域 个人。这项建议旨在通过调查来证实和扩大这一发现 星形胶质细胞亚群、其分子特征及其与其他细胞类型的关系 在大脑的多个区域存在种族差异。通过组合单一的- 核糖核酸测序、空间转录、免疫组织化学和系统 生物学方面，我们建议创建星形胶质细胞的不同分布图 “抗性”和“敏感”个体的亚群及其与病理的空间关系 和其他细胞类型，以及参与星形胶质细胞介导的候选基因和途径 对tau病理的抵抗。归根结底，描述特定的 星形胶质细胞亚群、它们的相互作用和参与抗性个体的途径 可能会找到治疗方法来缓解AD患者的认知能力下降 病理学。

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.