Mass spectrometry and multiplexed immunofluorescence imaging of metabolic and proteomic contributors to selective neuronal vulnerability in Alzheimer's disease

阿尔茨海默病选择性神经元脆弱性的代谢和蛋白质组学贡献者的质谱分析和多重免疫荧光成像

• 批准号: 10515902
• 负责人: PARAG Kumar MALLICK
• 金额: $ 88.09万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515902
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Architecture; Area; Autopsy; Brain; Brain region; Cells; Chimera organism; Clinical; Computer Vision Systems; Data; Data Set; Detection; Development; Disease; Disease Progression; Energy Metabolism; Environment; Environmental Risk Factor; Exhibits; Experimental Models; Feasibility Studies; Future; Genetic; Goals; Human; Image; Imaging Device; Imaging Techniques; Immunofluorescence Immunologic; In Situ; Individual; Inflammation; Intervention; Knowledge; Laboratories; Location; Machine Learning; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Modality; Modeling; Molecular; Molecular Profiling; Morphology; Mus; Myelin; Neighborhoods; Neocortex; Nerve Degeneration; Neuroglia; Neurons; Organoids; Outcome Study; Oxidative Stress; Pathologic; Pathway interactions; Pattern; Phase; Phenotype; Pilot Projects; Population; Predisposition; Prefrontal Cortex; Proteins; Proteomics; Pyramidal Cells; Resistance; Resolution; Senile Plaques; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Slide; Spatial Distribution; Specimen; Supervision; Testing; Tissue Microarray; Tissue Stains; Tissues; Validation; Visual; area striata; base; cell type; comparative; density; differential expression; gray matter; hippocampal pyramidal neuron; humanized mouse; imaging modality; imaging study; insight; large datasets; mass spectrometric imaging; metabolic imaging; metabolic profile; molecular imaging; molecular phenotype; neocortical; neuroinflammation; neuropathology; novel; protein aggregation; regional difference; resilience; risk variant; small molecule; spatial relationship; tau aggregation; tool; transcriptomics; white matter

We aim to uncover metabolic and protein signaling pathways contributing to the regional vulnerability of neocortical pyramidal neurons in Alzheimer's disease and to identify novel targets for detection and intervention. We will compare the prefrontal cortex, a neocortical brain area afflicted by neuropathology early in Alzheimer's disease, with the primary visual cortex, a brain area that is relatively spared. We will use mass spectrometric imaging in combination with segmentation analyses, to identify spatial changes of small molecules and proteins in postmortem brain sections prepared from these neocortical areas from donors at various clinical and pathological stages of Alzheimer's disease compared to controls. Then, we will apply multiplexed immunofluorescence imaging on sequential sections from the same specimens, to obtain information on cellular and microenvironment changes in and around vulnerable neocortical neurons during disease progression, correlated with the clinical severity, degree and location of neuropathological changes, and the risk genotype. Further, we will register the data from both imaging techniques to identify metabolic pathways and protein signaling changes at the regional, laminar and cellular level and to locate covariation in molecular and cellular phenotypes contributing to Alzheimer's disease vulnerability. In addition to generating a comprehensive dataset of the cellular and molecular changes at various stages of Alzheimer's disease, these studies will involve the development, validation, and dissemination of novel tools for analysis of large datasets generated using two powerful imaging tools, one that detects hundreds of analytes with the possibility of detecting previously unknown contributors to disease and the other that provides higher resolution with a select set of known markers. In the long term, the data generated from these studies could provide the basis for testing novel disease- modifying treatments by cell-type specific targeting of identified metabolic pathways using experimental models, such as brain organoids to replicate cortical lamination with human neurons or humanized mouse chimeras to model interactions between neurons and non-neuronal cell types.

我们旨在发现有助于区域脆弱性的代谢和蛋白质信号通路 阿尔茨海默氏病中的新皮层锥体神经元，并鉴定出新的检测靶 干涉。我们将比较前额叶皮层，这是一种受神经病理折磨的新皮层脑区域 在阿尔茨海默氏病早期，主要视觉皮层是一个相对幸免的大脑区域。我们将 将质谱成像与分割分析结合使用，以识别空间变化 从这些新皮质区域制备的尸体脑切片中的小分子和蛋白质的 与对照组相比，在阿尔茨海默氏病的各种临床和病理阶段的供体。然后，我们 将在从相同标本的顺序切片上应用多路复用的免疫荧光成像， 获取有关细胞和微环境在脆弱的新皮质中和周围发生变化的信息 疾病进展过程中的神经元与临床严重程度，程度和位置相关 神经病理学的变化和风险基因型。此外，我们将从两次成像中注册数据 鉴定代谢途径和蛋白质信号传导在区域，层流和 细胞水平并定位有助于阿尔茨海默氏症的分子和细胞表型中的协方差 疾病脆弱性。除了生成细胞和分子的综合数据集 在阿尔茨海默氏病的各个阶段的变化，这些研究将涉及开发，验证， 并传播新的工具，用于分析使用两个强大成像生成的大型数据集 工具，一种检测数百个分析物具有检测以前未知的可能性的工具 疾病的贡献者，另一种可提供更高分辨率的已知标记。 从长远来看，这些研究产生的数据可以为测试新型疾病的基础 - 通过实验性，通过细胞类型的特异性靶向对鉴定的代谢途径进行修饰治疗 模型，例如大脑器官，用人神经元或人源性小鼠复制皮质层压 嵌合体建模神经元与非神经元细胞类型之间的相互作用。