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

基于成像质谱仪的阿尔茨海默病脑代谢组学分析 项目总结 阿尔茨海默病(AD)是最常见的神经退行性疾病。尽管多个基因和它们的 与AD发病机制相关的突变已有报道，但AD的致病机制仍然存在 难以捉摸。大多数AD研究的重点一直是针对选择性丢失的特定基因 神经元群。尽管如此，在理解反应性星形胶质细胞这一常见特征方面花费的努力却很少。 老年大脑中的损伤和疾病。最近，我们描述了一种反应性星形胶质细胞亚型 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)。 小胶质细胞的激活通过分泌神经递质促进星形胶质细胞向神经毒性反应性星形胶质细胞转化 IL-1、肿瘤坏死因子、C1q。用药物阻断小胶质细胞的激活，NLY01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。静息状态下小胶质细胞和星形胶质细胞向反应性细胞的转化 一种与细胞内能量代谢和脂质成分的变化密切相关。静息小胶质细胞 主要依靠氧化磷酸化来产生能量。当小胶质细胞的代谢从 氧化磷酸化到糖酵解，小胶质细胞被激活。这一变化随后转换为休息 星形胶质细胞到反应性星形胶质细胞，增加了他们的葡萄糖消耗。APOE和APOE中的长链饱和脂类 星形胶质细胞分泌的APOJ也被报道显示出神经毒性。因此，理解 小胶质细胞、星形胶质细胞和神经元在神经变性过程中的代谢变化可能是 加深对AD发病机制的理解。基于成像质谱学的代谢组学分析 将提供大脑中细胞类型和特定区域代谢变化的视图。研究代谢组学 针对特定细胞类型的变化，我们提出了三个具体目标。(目标1)我们将研究区域-和 小鼠脑内小胶质细胞-星形胶质细胞-神经元轴的细胞类型特异性代谢变化 淀粉样蛋白β的过度表达以及对病理性tau的反应。(目标2)我们将检查区域和细胞类型- 对照组和阿尔茨海默病患者死后脑的特定代谢变化。(目标3)我们将比较地区- 高表达淀粉样蛋白β的小鼠的细胞类型特异性脑代谢变化及其对 用PLX3397或NLY01治疗缺乏小胶质细胞激活的病理性tau。这个 这些目标的完成将提供对衰老过程中细胞型代谢组动力学的更好理解 过度表达的淀粉样蛋白β和病理性tau注射所介导的神经变性。这部小说 这项研究中获得的信息将为研究特定细胞类型的AD致病机制提供不可或缺的见解 并为开发针对小胶质细胞和星形胶质细胞的新阿尔茨海默病治疗方法提供了新的机会。 此外，这一策略还可以扩展到研究其他脑部疾病的发病机制。 1

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