Spatial analysis of regional, cell type and molecular hallmarks of Alzheimer's disease

阿尔茨海默病的区域、细胞类型和分子标志的空间分析

基本信息

批准号：
10112806
负责人：
Ed Lein
金额：
$ 94.58万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10112806
关键词：
Address Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Precursor Area Brain Brain region Cell Nucleus Cells Classification Clinical Data Deposition Disease Progression Fluorescent in Situ Hybridization Frequencies Future Gene Expression Gene Expression Profiling Generations Genes Genetic Transcription Goals Human Immunohistochemistry In Situ Hybridization Link Maps Measures Methods Molecular Nerve Degeneration Neuroglia Output Pathogenesis Pathologic Pathway interactions Phase Population Population Analysis Protein Analysis Proteins RNA RNA analysis Resistance Resolution Severities Severity of illness Standardization Technology Tissues Work aged aging brain base brain tissue cell type cellular targeting cholinergic neuron cohort data acquisition data analysis pipeline design epigenomics excitatory neuron hyperphosphorylated tau neuropathology progressive neurodegeneration protein aggregation protein biomarkers protein expression spatial relationship transcriptome transcriptomics

项目摘要

ABSTRACT (PROJECT 3) The molecular mechanisms underlying cellular vulnerability in Alzheimer’s disease are unclear. The objective of this project is to clarify the molecular mechanisms responsible for select cell vulnerability and pathogenesis by applying spatial methods for highly multiplexed RNA and protein analysis in Alzheimer’s-affected tissue sections. We will optimize and standardize platforms for multiplexed fluorescence in situ hybridization (mFISH) to examine AD-linked gene sets derived from single nucleus transcriptome analysis, as well as immunohistochemistry (IHC) to examine pathological protein markers in the context of cell type populations in intact human brain tissue. These methods will then be applied to Alzheimer’s disease tissues from brain regions affected in different levels of disease severity to understand 1) the spatial organization of transcriptomically-defined cell types in these brain regions and changes in this organization with disease severity (e.g. selective vulnerability or proliferation), 2) molecular pathways disrupted in Alzheimer’s disease in the context of specific cell types, and 3) the relationship between these affected cell types and the markers of Alzheimer’s pathology, such as amyloid precursor protein and hyperphosphorylated tau. These data generated by mFISH and IHC together will provide a high-resolution map of the cellular and molecular consequences of clinically typical Alzheimer’s disease and an enhanced view of Alzheimer’s pathology, as well as a powerful technology platform for future analyses of larger and more varied cohorts.

摘要（项目3）阿尔茨海默氏病中细胞脆弱性的分子机制尚不清楚。目标这个项目的是阐明负责选择细胞脆弱性和发病机理的分子机制通过在阿尔茨海默氏症组织中应用空间方法进行高度多重的RNA和蛋白质分析部分。我们将优化和标准化平台，用于多重荧光原位杂交（MFISH）检查从单核转录组分析中得出的广告连锁基因集，免疫组织化学（IHC）在细胞类型种群中检查病理蛋白标记物完整的人脑组织。然后，这些方法将应用于大脑的阿尔茨海默氏病时机在不同程度的疾病严重程度上影响的地区以了解1）这些大脑区域中的转录态定义的细胞类型以及该组织的疾病变化严重程度（例如，选择性脆弱性或增殖），2）在阿尔茨海默氏病中破坏的分子途径特定细胞类型的上下文，以及3）这些受影响的单元格类型与标记之间的关系阿尔茨海默氏病的病理，例如淀粉样蛋白前体蛋白和高磷酸化tau。这些数据生成通过MFISH和IHC一起，将提供一张高分辨率图的细胞和分子后果。临床上典型的阿尔茨海默氏病，并增强了阿尔茨海默氏病的看法用于将来分析更大和更多样化的队列的技术平台。