Geroscience metabolites beta-hydroxybutyrate and NAD+ linking inflammation and neuroenergetic failure in delirium

老年科学代谢物β-羟基丁酸和NAD与谵妄中的炎症和神经能量衰竭有关

• 批准号: 10626524
• 负责人: John C Newman
• 金额: $ 7.18万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626524
• 关键词: APP-PS1; Acute; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Area; Attention; Basic Science; Behavior; Behavioral; Biological Markers; Biology; Biology of Aging; Brain; Cells; Cerebrospinal Fluid; Cerebrum; Chronic; Clinical; Clinical Research; Cognitive deficits; Cohort Studies; Confusion; Conscious; Consumption; Cultured Cells; Data; Delirium; Dementia; Development; Elderly; Encephalitis; Energy Metabolism; Energy-Generating Resources; Enzymes; Failure; Fasting; Functional disorder; Genetic Models; Geroscience; Glucose; Goals; Hospitalization; Hospitals; Human; Hypoxia; Impairment; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Injections; Intervention; Ketone Bodies; Ketones; Knock-out; Knockout Mice; Lead; Link; Lipopolysaccharides; Macrophage Activation; Mediator of activation protein; Memory; Metabolic; Metabolic dysfunction; Metabolism; Microglia; Modeling; Molecular; Mus; NAD+ Nucleosidase; Neuronal Dysfunction; Neurons; Nicotinamide adenine dinucleotide; Operative Surgical Procedures; Oxidative Stress; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Postoperative Period; Predisposition; Prevention; Risk; Role; Sampling; Signal Transduction; Surgical complication; Syndrome; System; Testing; Work; analog; base; beta-Hydroxybutyrate; clinical development; cohort; disability; drug discovery; glucose metabolism; high risk; improved; in vitro Model; in vivo; innovation; ketogenic diet; macrophage; mortality risk; mouse model; neuroinflammation; physiologic stressor; postoperative delirium; prevent; resilience; sedative; small molecule

PROJECT SUMMARY Delirium is a geriatric syndrome of fluctuating confusion that is a common complication of surgery and hospitalization in older adults, and is associated with increased risk of death, disability, and dementia. People with Alzheimer's Disease and Related Dementias (ADRD) are at especially high risk for delirium. The pathophysiology of delirium is not well understood, but is thought to include neuroinflammation and brain energetic disruption. These features also link delirium to ADRD. Impaired cerebral glucose metabolism is a chronic feature of ADRD, and an acute feature of delirium. Similarly, chronic neuroinflammation is thought to be an important contributor to ADRD, and acute inflammation is associated with delirium. In this translational project we propose to test an innovative molecular link between acute-on-chronic brain inflammation and metabolic dysfunction, using cell systems, mouse models, and biospecimens from a human delirium cohort. Ketone bodies provide a non-glucose energy source for the brain during fasting, and ketone body metabolism remains intact in ADRD even with impaired glucose metabolism. We recently found that disrupted glucose metabolism is an important driver of behavioral changes in mouse models of delirium. We also recently showed that a ketogenic diet improves memory in both aging mice and an ADRD mouse model. We developed an innovative toolkit of compounds and genetic models to mechanistically study ketone bodies experimentally. We hypothesize that energetic support from ketone bodies might help compensate for inflammation-induced neuronal impairments in glucose metabolism. We also elucidated a new mechanism linking inflammation to metabolism, showing that activation of peripheral macrophages induces enzymes that degrade the key metabolic mediator NAD+. Inflammation-driven NAD+ depletion occurs chronically in aging and ADRD, and may occur acutely in delirium. We will use an inflammation model of delirium with normal mice and two ADRD models to test if ketone bodies or NAD+ can rescue acute delirium-like behavioral changes, and identify the relevant mechanisms (Aim 1). We will use cultured cells and an in vivo brain inflammation model to determine if activated microglia deplete NAD+ similarly to macrophages, and whether preventing this also rescues delirium-like behaviors (Aim 2). Finally, we will use cerebrospinal fluid samples from a large clinical study of postoperative delirium to determine how endogenous ketone body and NAD+ levels differ between patients with vs. without delirium (Aim 3). This collaborative project links basic science expertise in ketone body and NAD+ biology relevant to ADRD, with basic and clinical research expertise in delirium. It will open a new area of mechanistic study on inflammation-induced metabolic deficits in delirium, guiding development of translational interventions.

项目摘要 谵妄是一种波动性意识模糊的老年综合征，是手术的常见并发症， 老年人住院，并与死亡、残疾和痴呆的风险增加有关。人 患有阿尔茨海默病和相关痴呆症（ADRD）的人患谵妄的风险特别高。的 谵妄的病理生理学尚不清楚，但被认为包括神经炎症和大脑 能量破坏这些特征也将谵妄与ADRD联系起来。脑葡萄糖代谢受损是一种 ADRD的慢性特征和谵妄的急性特征。同样，慢性神经炎症被认为是 是ADRD的重要促成因素，急性炎症与谵妄相关。在这个翻译 我们计划测试慢性急性脑炎症和慢性脑炎症之间的创新分子联系， 代谢功能障碍，使用细胞系统，小鼠模型和来自人类谵妄队列的生物标本。 酮体在禁食期间为大脑提供非葡萄糖能量来源， 在ADRD中，即使葡萄糖代谢受损，代谢也保持完整。我们最近发现， 葡萄糖代谢是谵妄小鼠模型中行为变化的重要驱动因素。我们也 最近表明，生酮饮食可以改善衰老小鼠和ADRD小鼠模型的记忆力。我们 开发了一个创新的化合物和遗传模型工具包，以机械地研究酮体 实验性的我们假设来自酮体的能量支持可能有助于补偿 炎症诱导的葡萄糖代谢中的神经元损伤。我们还阐明了一种新的机制 将炎症与代谢联系起来，表明外周巨噬细胞的激活诱导了 降解关键代谢介质NAD+。炎症驱动的NAD+耗竭在衰老过程中长期发生， ADRD，可能在谵妄时急性发生。 我们将使用正常小鼠的谵妄炎症模型和两种ADRD模型来测试酮是否 体或NAD+可以挽救急性谵妄样行为变化，并确定相关机制（目的 1）。我们将使用培养的细胞和体内脑炎症模型，以确定是否激活小胶质细胞， 与巨噬细胞类似地消耗NAD+，以及预防这一点是否也能挽救谵妄样行为（Aim 2）。最后，我们将使用来自一项大型术后谵妄临床研究的脑脊液样本， 确定有与无谵妄患者之间内源性酮体和NAD+水平的差异 (Aim 3）。该合作项目将酮体和NAD+生物学的基础科学专业知识与以下方面联系起来： ADRD，具有谵妄的基础和临床研究专长。这将为化学反应机理的研究开辟一个新的领域。 炎症诱导的代谢缺陷谵妄，指导翻译干预的发展。