Project 3: 3-D Molecular Atlas of cerebral amyloid angiopathy in the aging brain with and without co-pathology

项目3：项目摘要/摘要 脑淀粉样血管病(CAA)是一种与年龄相关的血管病变，其中有沉积的 软脑膜和实质血管壁中的淀粉样蛋白-β蛋白。它可以在联想中看到 阿尔茨海默病-神经病理改变(AD-NC)，以及隔离。在本研究中，我们将重点放在 关于CAA如何改变大脑三个已知的不同区域的局部细胞环境 对CAA的不同易感性：颞上回、背外侧前额叶皮质和距骨皮质。 我们将比较单独的CAA和与AD-NC增加的负担相关的CAA。有非常多的 关于CAA如何在衰老过程中改变局部细胞环境的有限分子数据，尽管我们知道 在没有任何其他蛋白质病的情况下，CAA可以导致认知能力下降，但也可以加剧 伴有蛋白质病的认知功能减退。因此，这个项目的首要目标是生成一个空间地图集 CAA和不同严重程度的阿尔茨海默病患者的细胞类型和分子特征-- 神经病理改变(AD-NC)以评估近程和远期，以及多个 死后人脑组织细胞成分和特征的病理学研究。我们假设 CAA对附近的细胞类型组成和蛋白质特征有局部影响，影响所有元素 神经血管单位(NVU)的影响，而CAA的影响因并存而加剧 AD蛋白病。在这个项目中，我们提出了一种新的但可证明可伸缩的蛋白质组合 和基因表达方法，研究大量(300微米厚)的人体组织 CAA与AD-NC和不与AD-NC的组合。这将允许生成一份高分辨率的地图集 老年人脑组织中与CAA相关的细胞类型和基因表达特征 许多现有的和正在进行的人类免疫领域的整体和单核rna-seq研究 神经退行性变研究

PROJECT 3: PROJECT SUMMARY/ABSTRACT Cerebral amyloid angiopathy (CAA) is an age-associated vasculopathy in which there is deposition of amyloid-β protein in the walls of leptomeningeal and parenchymal blood vessels. It can be seen in association with Alzheimer’s disease- neuropathologic change (AD-NC), as well as in isolation. In this study, we focus on how CAA alters the local cellular environment in three distinct regions of the brain that are known to have variable susceptibility to CAA: superior temporal gyrus, dorsolateral prefrontal cortex, and calcarine cortex. We will compare CAA in isolation and in association with increasing burden of AD-NC. There is extremely limited molecular data on how CAA can modify the local cellular environment in aging, although we know CAA can cause cognitive decline in the absence of any other proteinopathy, but can also exacerbate the cognitive decline with proteinopathy. Thus, the overarching goal of this project is to generate a spatial atlas of cell types and molecular signatures in cases with CAA and variable severities of Alzheimer’s Disease- Neuropathologic Change (AD-NC) to assess short- and long-range, and interactive effects of multiple pathologies on cellular composition and signatures from post-mortem human brain tissue. We hypothesize that CAA has local effects on the cell type composition and protein signature nearby, affecting all elements of the neurovascular unit (NVU), and that the effects of CAA are exacerbated by the presence of comorbid AD proteinopathies. For this project we propose a combination of novel but demonstrably scalable protein and gene expression approaches, to study large volumes (300-micron thickness) of human tissue with combinations of CAA with and without AD-NC. This will allow for the generation of a high-resolution atlas of cell types and gene expression signatures in aged human brain tissue that relate to CAA, complementing many of the existing and ongoing bulk and single-nucleus RNA-seq studies in the field of human neurodegeneration research