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: 10632035
• 负责人: John C Newman
• 金额: $ 76.91万
• 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/10632035
• 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; Compensation; Confusion; Conscious; Consumption; Cultured Cells; Data; Delirium; Dementia; Development; Elderly; Encephalitis; Energy Metabolism; Energy-Generating Resources; Enzyme Induction; 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; Link; Lipopolysaccharides; Macrophage; Macrophage Activation; Mediator; 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; beta-Hydroxybutyrate; clinical development; cohort; disability; drug discovery; glial activation; glucose metabolism; high risk; improved; in vitro Model; in vivo; innovation; ketogenic diet; mortality risk; mouse model; neuroinflammation; physiologic stressor; postoperative delirium; prevent; resilience; sedative; small molecule; theories

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 ir妄是一种波动混乱的老年综合症，是手术的常见并发症和 老年人住院，与死亡，残疾和痴呆症的风险增加有关。人们 阿尔茨海默氏病和相关痴呆症（ADRD）的ir妄风险尤其高。这 妄想的病理生理学尚不清楚，但被认为包括神经炎症和大脑 充满活力的破坏。这些功能还将del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del妄的急性特征。同样，慢性神经炎症也被认为是 成为ADRD的重要因素，并且急性炎症与del妄有关。在这种翻译中 我们建议的项目旨在测试急性智力脑炎症和 代谢功能障碍，使用人类ir妄同伴的细胞系统，小鼠模型和生物测量。 酮体在禁食过程中为大脑提供非葡萄糖能源，酮体 即使葡萄糖代谢受损，代谢仍然完好无损。我们最近发现这被干扰 葡萄糖代谢是小鼠del妄模型中行为变化的重要驱动力。我们也是 最近表明，生酮饮食可改善老化小鼠和ADRD小鼠模型的记忆力。我们 开发了一种创新的化合物和遗传模型的工具包，以机械学研究酮体 实验。我们假设酮体的充满活力的支持可能有助于补偿 炎症引起的葡萄糖代谢中的神经元损伤。我们还阐明了一种新机制 将炎症与代谢联系起来，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 Adrd，并且可能在del妄中急性发生。 我们将使用正常小鼠和两个ADRD模型使用del妄模型来测试酮是否 身体或NAD+可以挽救急性ir妄样的行为变化，并确定相关机制（AIM 1）。我们将使用培养的细胞和体内脑炎症模型来确定是否活化的小胶质细胞 耗尽NAD+类似于巨噬细胞，以及防止这种情况也可以挽救类似del妄的行为（AIM 2）。最后，我们将使用术后del妄的大型临床研究到脑脊液样品到 确定内源性酮体和NAD+水平在没有de妄的患者之间如何差异 （目标3）。这个协作项目链接了酮体和NAD+生物学的基础科学专业知识 ADRD，具有del妄的基本和临床研究专业知识。它将为机械研究的新领域开放 炎症引起的del妄的代谢缺陷，指导转化干预措施的发展。