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：项目总结/摘要 阿尔茨海默氏病（AD）是最普遍的衰老性神经退行性疾病，并且导致多种 其中最突出的是进行性认知能力下降。而主要的病理性 与AD相关的蛋白质病是β淀粉样蛋白（斑块）和tau蛋白（神经胶质细胞）的聚集 缠结），这些蛋白质病的外观、密度和分布显示出实质的异质性 在个体和大脑区域之间。此外，个体经常表现出这两种症状的同时出现 具有其他蛋白质聚集体的蛋白质病，如TDP 43和α-突触核蛋白;后两者是 主要与肌萎缩侧索硬化症、额颞叶痴呆和 帕金森氏病，但它们在AD中的发生并不罕见。从我们的大规模单核RNA测序 通过对死后组织的研究，我们已经确定了特定的细胞特征/推定亚型， 丰度与缠结和斑块有关。然而，这些大块和单核实验 这些方法不保留关于这些细胞类型如何在周围定位（或不定位）的空间信息。 病理性夹杂物，从而产生一个不完整的图片，如何细胞结构的老年人 大脑在AD病理学的存在下发生改变。在这里，我们的目的是检查空间分布和 这些细胞类型的组织直接在完整的人脑组织使用高度多路复用的空间方法。 我们提出了一种新的，但可证明可扩展的蛋白质和基因表达方法的组合， 研究大量（300微米厚）具有这些蛋白质病组合的人体组织。 这些大量的研究是必要的蛋白质聚集体的“高度本地”的全面影响 环境具体地说，我们使用高度多重抗体染色和全基因组 空间转录组学方法来检验我们关于神经元和神经胶质细胞重组的假设 病理性包涵体周围的类型，重点是两种主要的AD相关蛋白病（淀粉样蛋白 和tau）。最终，这将产生一个高分辨率的细胞类型和基因表达特征图谱， 在AD中常见的蛋白质聚集体的存在下改变的老年人脑组织， 补充了许多现有的和正在进行的批量和单核RNA-seq研究领域的 人类神经退化研究