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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

基本信息

批准号：
10256620
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
项目类别：
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/10256620
关键词：
APP-PS1 Acute Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目总结