Project 2: 3-D Molecular atlas of AD proteinopathy

项目 2：AD 蛋白病的 3-D 分子图谱

• 批准号: 10555898
• 负责人: Vilas Menon
• 金额: $ 56.28万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555898
• 关键词: 3-Dimensional; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyotrophic Lateral Sclerosis; Antibodies; Appearance; Atlases; Autopsy; Brain region; Cell Nucleus; Cells; Cellular Structures; Complement; Disease; Environment; Female; Frontotemporal Dementia; Gene Expression; Gene Expression Profile; Heterogeneity; Human; Impaired cognition; Individual; Maps; Methods; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Parkinson Disease; Pathologic; RNA; Research; Resolution; Spatial Distribution; Stains; Symptoms; Thick; Tissues; abeta accumulation; aged; aging brain; alpha synuclein; brain tissue; cell type; density; genome-wide; human tissue; male; novel; protein TDP-43; protein aggregation; protein expression; single nucleus RNA-sequencing; tau Proteins; transcriptomics; vaping

PROJECT 2: PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease of aging, and results in a variety of symptoms, the most prominent of which is progressive cognitive decline. Whereas the primary pathological proteinopathies associated with AD are aggregates of amyloid-beta (plaques) and tau (neurofibrillary tangles), the appearance, density, and distribution of these proteinopathies shows substantial heterogeneity across individuals and brain regions. In addition, individuals often display co-occurrence of these two proteinopathies with other protein aggregates such as TDP43 and alpha-synuclein; these latter two are primarily associated with diseases such as Amyotrophic Lateral Sclerosis, Frontotemporal Dementia and Parkinson’s Disease, but their occurrence in AD is not rare. From our bulk and single-nucleus RNA-seq studies on post-mortem tissue, we have identified specific cellular signatures/putative subtypes whose abundance is associated with tangles and plaques. However, these bulk and single-nucleus experimental approaches do not preserve spatial information about how these cell types are localized (or not) around pathological inclusions, and thus generate an incomplete picture of how the cellular structure of the aged brain is altered in the presence of AD pathology. Here, we aim to examine the spatial distribution and organization of these cell types directly in intact human brain tissue using highly-multiplexed spatial methods. 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 these proteinopathies. These large volumes are necessary to study the full impact of protein aggregates on the “highly local” environment. Specifically, we use a combination of highly multiplexed antibody staining and genome-wide spatial transcriptomics methods to examine our hypothesis on the reorganization of neuronal and glial cell types around pathological inclusions, with a focus on the two major AD-associated proteinopathies (amyloid and tau). Ultimately, this will generate a high-resolution atlas of cell types and gene expression signatures in aged human brain tissue that are altered in the presence of protein aggregates commonly found in AD, complementing many of the existing and ongoing bulk and single-nucleus RNA-seq studies in the field of human neurodegeneration research.

项目2：项目摘要/摘要 阿尔茨海默氏病（AD）是衰老的最普遍的神经退行性疾病，导致多样性 症状，其中最突出的是渐进的认知能力下降。而主要的病理 与AD相关的蛋白质病是淀粉样蛋白β（斑块）和Tau（神经原纤维）的聚集体 缠结），这些蛋白质病的外观，密度和分布显示出很大的异质性 跨个体和大脑区域。此外，个人经常显示这两个的共同出现 蛋白质疾病与其他蛋白质聚集体，例如TDP43和α-核蛋白；后两个是 主要与肌萎缩性侧索硬化症，额颞痴呆和等疾病有关 帕金森氏病，但它们在广告中的发生并不罕见。从我们的散装和单核RNA-seq 关于死后组织的研究，我们已经确定了特定的细胞特征/推定的亚型 抽象与缠结和斑块有关。但是，这些散装和单核实验 方法不能保留有关这些细胞类型如何（或不存在）的空间信息 病理夹杂物，从而产生不完整的描述年龄的细胞结构 在存在AD病理学的情况下，大脑会改变。在这里，我们旨在检查空间分布和 这些细胞类型的组织直接在完整的人脑组织中使用高度多形的空间方法组织。 我们提出了新颖但展示可扩展蛋白和基因表达方法的组合 研究了这些蛋白质病的组合的大量人体组织（300微米厚度）。 这些庞大的体积对于研究蛋白质聚集体对“高度局部”的全部影响是必要的 特别是，我们使用高度多重抗体染色和全基因组的组合 空间转录组学方法是检查我们关于神经元和神经胶质细胞重组的假设 围绕病理夹杂物的类型，重点是两种主要的广告相关蛋白质病（淀粉样蛋白 和tau）。最终，这将产生细胞类型和基因表达特征的高分辨率地图集 在AD中常见的蛋白质聚集体存在下改变的老年人脑组织 在该领域完成许多现有的和正在进行的散装和单核RNA-seq研究 人类神经退行性研究。