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

• 批准号: 10516253
• 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
• 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/10516253
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' 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 (Brain); Human; Injections; Injury; Interleukin-1; 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; base; 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

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 阿尔茨海默病（AD）是最常见的神经退行性疾病。尽管多个基因及其 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 难以捉摸。大多数 AD 研究的重点是选择性丧失特定的 神经元群。尽管如此，在理解反应性星形胶质细胞上花费的精力却较少，这是一个常见的特征 导致老年大脑损伤和疾病。最近，我们描述了反应性星形胶质细胞的一种亚型 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 IL-1α、TNFα 和 C1q。 NLY01 通过药物阻断小胶质细胞激活，阻止星形胶质细胞转化为 反应性星形胶质细胞提供神经保护。静息小胶质细胞和星形胶质细胞向反应性细胞的转化 与细胞内能量代谢和脂质组成的变化密切相关。静息小胶质细胞 主要依靠氧化磷酸化来产生能量。当小胶质细胞代谢从 氧化磷酸化到糖酵解，小胶质细胞被激活。此更改随后将休息 星形胶质细胞转变为反应性星形胶质细胞，从而增加其葡萄糖消耗。 APOE 中的长链饱和脂质和 据报道，星形胶质细胞分泌的 APOJ 也具有神经毒性。因此，了解 在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 有助于更深入地了解 AD 发病机制。基于成像质谱的代谢组学分析 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 以细胞类型特定的方式发生变化，我们提出了三个具体目标。 （目标 1）我们将检查区域和 小鼠大脑小胶质细胞-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淀粉样蛋白并对病理性 tau 蛋白做出反应。 （目标 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淀粉样蛋白的小鼠和细胞类型特异性脑代谢组变化以及对 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。这 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 过度表达的 β 淀粉样蛋白和病理性 tau 注射介导的神经退行性变。小说 本研究中获得的信息将为细胞类型特异性 AD 致病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，该策略可以扩展到研究其他脑部疾病的发病机制。 1