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: 10037630
• 负责人: John C Newman
• 金额: $ 80.95万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10037630
• 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; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Postoperative Period; Predisposition; Prevention; Risk; Role; Sampling; Signal Transduction; Structure; 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.

项目概要 谵妄是一种波动性意识模糊的老年综合征，是手术和手术的常见并发症。 老年人住院，并与死亡、残疾和痴呆的风险增加相关。人们 患有阿尔茨海默病和相关痴呆症 (ADRD) 的人发生谵妄的风险特别高。这 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。这些特征还将谵妄与ADRD联系起来。脑葡萄糖代谢受损是 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 ADRD 的重要促成因素，而急性炎症与谵妄有关。在这个翻译中 我们建议测试慢性脑炎症与急性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样本。 酮体在禁食期间为大脑提供非葡萄糖能量来源，酮体 即使葡萄糖代谢受损，ADRD 中的代谢仍保持完整。我们最近发现，中断 葡萄糖代谢是谵妄小鼠模型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 开发了化合物和遗传模型的创新工具包，用于机械研究酮体 实验性地。我们假设酮体的能量支持可能有助于补偿 炎症引起的葡萄糖代谢神经元损伤。我们还阐明了一种新机制 将炎症与新陈代谢联系起来，表明外周巨噬细胞的激活会诱导酶 降解关键代谢介质 NAD+。炎症驱动的 NAD+ 耗竭在衰老和衰老过程中长期发生 ADRD，并且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个 ADRD 模型来测试酮是否 身体或 NAD+ 可以挽救急性谵妄样行为变化，并确定相关机制（Aim 1）。我们将使用培养细胞和体内脑炎症模型来确定小胶质细胞是否被激活 与巨噬细胞类似地消耗 NAD+，以及阻止这种情况是否也能挽救类似谵妄的行为（目标 2）。最后，我们将使用来自术后谵妄大型临床研究的脑脊液样本来 确定有谵妄患者与无谵妄患者之间内源性酮体和 NAD+ 水平的差异 （目标 3）。该合作项目将酮体和 NAD+ 生物学相关的基础科学专业知识联系起来 ADRD，具有谵妄方面的基础和临床研究专业知识。它将开辟一个新的机理研究领域 炎症引起的谵妄代谢缺陷，指导转化干预措施的发展。