Imaging Mass Spectrometry-Based Metabolomic Analysis of the Alzheimer's Brain

基于成像质谱的阿尔茨海默病大脑代谢组学分析

基本信息

批准号：
10705238
负责人：
VALINA L. DAWSON
金额：
$ 81.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10705238
关键词：
Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Astrocytes Autopsy Brain Brain Diseases Brain region CSF1R gene Cells Cerebellum Cognitive deficits Complement 1q Complex Consumption Disease Energy Metabolism Exposure to Genes Glucose Glycolysis Heterogeneity Hippocampus Human Injections Injury Interleukin-1 alpha Link Lipids Mass Spectrum Analysis Mediating Metabolic Metabolism Microglia Monitor Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurons Oxidative Phosphorylation Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pharmaceutical Preparations Play Population Process Production Ramp Reporting Research Rest Role Senile Plaques System TNF gene Therapeutic Toxic effect aged aging brain brain tissue cell type glial activation human disease in vivo inhibitor insight mass spectrometric imaging metabolome metabolomics neuroprotection neurotoxic neurotoxicity novel overexpression prevent response saturated fat tau Proteins

项目摘要

IMAGING MASS SPECTROMETRY-BASED METABOLOMIC ANALYSIS OF THE ALZHEIMER'S BRAIN PROJECT SUMMARY Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Although multiple genes and their mutations linked to AD pathogenesis have been reported, the pathogenic mechanisms of AD still remain elusive. The focus of the majority of AD research has been targeted towards the selective loss of specific neuronal populations. Still, less effort has been spent in understanding reactive astrocytes, a feature common to injury and disease in the aged brain. Recently, we described a subtype of reactive astrocytes that are observed in various human neurodegenerative diseases, including AD and Parkinson's disease (PD). Activation of microglia leads to the conversion of astrocytes into neurotoxic reactive astrocytes via secretion of IL-1, TNF, and C1q. Blocking microglia activation with the drug, NLY01 prevented astrocyte conversion to reactive astrocytes providing neuroprotection. The conversion of resting microglia and astrocytes to reactive ones is deeply related to changes in energy metabolism and lipid composition in the cell. Resting microglia mainly rely on oxidative phosphorylation for energy production. When microglia metabolism converts from oxidative phosphorylation to glycolysis, microglia are activated. This change subsequently converts resting astrocytes to reactive ones ramping up their glucose consumption. Long-chain saturated lipids in APOE and APOJ secreted by astrocytes also have been reported to show neurotoxicity. Therefore, understanding metabolomic changes in microglia, astrocytes, and neurons during the course of neurodegeneration is likely to provide a deeper understanding of AD pathogenesis. Imaging mass spectrometry-based metabolomic analysis will provide a view of cell-type and region-specific metabolomic changes in the brain. To study metabolomic changes in a cell-type-specific manner, we propose three specific aims. (Aim 1) We will examine region- and cell-type-specific metabolomic changes in the microglia-astrocyte-neuron axis in the brain of mice overexpressing amyloid β and in response to pathologic tau. (AIM 2) We will examine region- and cell-type- specific metabolomic changes in control and AD human post-mortem brains. (Aim 3) We will compare region- and cell-type-specific brain metabolomic changes of mice overexpressing amyloid β and in response to pathologic tau with the ones lacking microglial activation by the treatment with PLX3397 or NLY01. The completion of these aims will provide a better understanding of cell-type metabolome dynamics during aging and neurodegeneration mediated by overexpressed amyloid β and pathologic-tau injection. The novel information acquired in this study will provide indispensable insights into cell-type-specific AD pathogenic mechanisms and offer new opportunities to develop new AD treatments targeting microglia and astrocytes. Furthermore, this strategy can be expanded to study the pathogenesis of other brain diseases. 1

基于质谱的成像质谱法代谢组分析对阿尔茨海默氏症的大脑项目摘要阿尔茨海默氏病（AD）是最普遍的神经退行性疾病。虽然多个基因及其已经报道了与AD发病机理有关的突变，AD的致病机制仍然保持难以捉摸。大多数AD研究的重点是针对特定的选择性损失的目标神经元种群。尽管如此，在理解反应性星形胶质细胞上花费的努力减少了，这是一个常见的功能老年大脑的损伤和疾病。最近，我们描述了反应性星形胶质细胞的亚型在包括AD和帕金森氏病（PD）在内的各种人类神经退行性疾病中观察到。小胶质细胞的激活导致星形胶质细胞通过分泌转化为神经毒性反应性星形胶质细胞 IL-1，TNF和C1Q。用药物阻断小胶质细胞激活，NLY01阻止了星形胶质细胞转换为可反应性星形胶质细胞提供神经保护作用。静息小胶质细胞和星形胶质细胞转化为反应性与细胞中能量代谢和脂质组成的变化密切相关。静止的小胶质细胞主要依靠氧化磷酸化来产生能量。当小胶质细胞代谢转换为对糖酵解，小胶质细胞的氧化磷酸化被激活。此更改随后将休息转换星形胶质细胞使反应性增强其葡萄糖消耗。 ApoE和据报道，由星形胶质细胞分泌的APOJ表现出神经毒性。因此，理解在神经退行性过程中，小胶质细胞，星形胶质细胞和神经元的代谢组变化很可能提供对AD发病机理的更深入的了解。基于质谱的成像质谱法分析将提供大脑中细胞类型和区域特异性代谢组变化的视图。研究代谢组学我们提出了三个特定目标，以细胞类型的特异性方式变化。（目标1）我们将检查区域和地区小鼠大脑中小胶质细胞 - 核细胞神经元轴的细胞型特异性代谢组变化过表达淀粉样β并响应病理tau。（AIM 2）我们将检查区域和细胞类型 - 对照和AD人类后大脑的特定代谢组变化。（目标3）我们将比较区域 - 过表达淀粉样β的小鼠的细胞型特异性脑代谢组变化，并响应于病理tau与PLX3397或NLY01治疗缺乏小胶质细胞激活的tau。这这些目标的完成将更好地理解衰老过程中细胞类型的代谢组动力学和神经变性是由过表达的淀粉样蛋白β和病理-TAU注射介导的。小说本研究中获得的信息将为细胞类型特异性AD致病性提供必不可少的见解机制并提供了新的机会来开发针对小胶质细胞和星形胶质细胞的新广告处理。此外，可以扩展该策略以研究其他脑部疾病的发病机理。 1