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

基于成像质谱的阿尔茨海默病大脑代谢组分析项目概要阿尔茨海默氏病（AD）是最常见的神经退行性疾病，尽管它与多种基因及其相关。与AD发病机制相关的突变已被报道，AD的致病机制仍然存在大多数 AD 研究的重点是特定的选择性丧失。尽管如此，在理解反应性星形胶质细胞这一常见特征方面却花费了较少的精力。最近，我们描述了一种反应性星形胶质细胞的亚型。在各种人类神经退行性疾病中观察到，包括 AD 和帕金森病 (PD)。小胶质细胞的激活导致星形胶质细胞通过分泌 NLY01 通过药物阻断 IL-1α、TNFα 和 C1q 来阻止星形胶质细胞转化为星形胶质细胞。提供神经保护的反应性星形胶质细胞将静息的小胶质细胞和星形胶质细胞转化为反应性星形胶质细胞。与细胞中能量代谢和脂质组成的变化密切相关。小胶质细胞代谢转化时主要依靠氧化磷酸化来产生能量。氧化磷酸化转变为糖酵解，小胶质细胞被激活，这种变化随后转变为静止状态。星形胶质细胞转变为反应性星形胶质细胞，增加了 APOE 和长链饱和脂质的消耗。据报道，星形胶质细胞分泌的 APOJ 也表现出神经毒性，因此需要了解。神经退行性变过程中小胶质细胞、星形胶质细胞和神经元的代谢组变化可能与基于成像质谱的代谢组学分析有助于更深入地了解 AD 发病机制。将提供大脑中细胞类型和区域特异性代谢组变化的视图来研究代谢组。以特定于细胞类型的方式发生变化，我们提出了三个具体目标（目标 1）我们将检查区域和区域。小鼠大脑中小胶质细胞-星形胶质细胞-神经元轴的细胞类型特异性代谢组变化过度表达β淀粉样蛋白并响应病理性 tau (AIM 2) 我们将检查区域和细胞类型。对照和 AD 人类死后大脑中的特定代谢组变化（目标 3）我们将比较区域 - 过度表达β淀粉样蛋白的小鼠的细胞类型特异性脑代谢变化以及对通过 PLX3397 或 NLY01 治疗，病理性 tau 蛋白与缺乏小胶质细胞激活的 tau 蛋白相结合。完成这些目标将有助于更好地了解衰老过程中的细胞类型代谢组动力学 β 淀粉样蛋白过度表达和病理性 tau 注射介导的神经退行性疾病。本研究中获得的信息将为细胞类型特异性 AD 致病性提供不可或缺的见解机制，并为开发针对小胶质细胞和星形胶质细胞的新 AD 治疗方法提供了新的机会。此外，这种策略可以扩展到研究其他脑部疾病的发病机制。 1