Mechanisms of the signaling metabolite β-hydroxybutyrate in Alzheimer's disease and the aging brain

信号代谢物β-羟基丁酸在阿尔茨海默病和大脑老化中的作用机制

基本信息

批准号：
10882007
负责人：
John C Newman
金额：
$ 4.51万
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：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10882007
关键词：
Acetoacetates Acetylation Acute Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Binding Biological Biological Assay Biological Markers Biology Brain C57BL/6 Mouse Carbohydrates Cell physiology Cells Chemicals Clinical Trials Cognitive Complex Data Diet Disease Electrophysiology (science)Elements Energy Metabolism Enzyme Inhibition Enzymes Epigenetic Process Epilepsy Esters Exercise Fasting Functional disorder Gene Expression Genetic Geroscience Glucose Glutamates Hippocampus Histone Deacetylase Inhibitor Histones Individual Inflammasome Inflammation Intervention Intraperitoneal Injections Investigation Ketone Bodies Ketones Knock-out Laboratories Laboratory mice Link Lipids Longevity Macronutrients Nutrition Maps Mass Spectrum Analysis Memory Memory Loss Memory impairment Metabolic Metabolism Molecular Molecular Target Mus Neurons Oral Pathologic Pathology Pathway interactions Patients Phenotype Post-Translational Protein Processing Prevention Production Proteins Proteome Proteomics Science Signal Transduction Site System Testing Time Tissues Visuospatial Wild Type Mouse Work age related aging brain beta-Hydroxybutyrate brain dysfunction brain health combinatorial design dietary dietary restriction effective intervention effective therapy enantiomer epileptiform feeding functional decline gamma-Aminobutyric Acid human old age (65+)improved in vitro Assay in vivo inhibitor innovation ketogenesis ketogenic diet mouse model neuroprotection new therapeutic target normal aging nutrition oxidation pharmacologic prevent protein function receptor resilience response senescence small molecule targeted agent targeted treatment tau Proteins tool translational study

项目摘要

PROJECT SUMMARY Signaling metabolites are small molecules with routine functions in cellular energy metabolism that also act as signals to regulate diverse cellular pathways in response to a changing energy state. Signaling metabolites link nutrition to aging. Many of the emerging geroscience therapies that target mechanisms of aging have come from the discovery and understanding of signaling metabolites. The ketone body β-hydroxybutyrate (BHB) is a new signaling metabolite. It is produced during fasting, dietary restriction, exercise, or carbohydrate restriction to keep the body's tissues supplied with energy when glucose is scarce. We now have growing evidence that it also functions as a signal, by inhibiting enzymes, binding directly to proteins as a post-translational modification, and activating receptors. Through its signaling activities, BHB regulates gene expression, inflammation, metabolism, senescence, and other cellular activities important to both aging and Alzheimer's disease (AD). We recently showed for the first time that ketogenic diet (KD), which stimulates endogenous production of BHB similar to fasting, improves survival in aging mice and prevents age-related declines in memory. We also found that KD improves memory in the hAPPJ20 AD mouse model, and reduces abnormal epileptiform discharges that contribute to memory decline. KD is a complex intervention, and though it is now being studied in clinical trials of AD, a better understanding of which aspects of KD are most helpful should lead to better targeted and more effective therapies. We have successfully developed an innovative toolset of dietary, chemical, and genetic tools to isolate the individual components of KD, including carbohydrate restriction, BHB, energy provision by BHB, and cellular signaling activities of BHB. We will use these tools to uncover the specific mechanisms by which BHB improves memory in normal aging and in AD mice (Aim 1), and reduces epileptiform discharges in AD mice (Aim 2). We will characterize key molecular changes that BHB causes in the proteomic landscape of the brain, including mapping the acetylome and new BHBylome (Aim 3). This project combines expertise in both geroscience and AD with a deep understanding of BHB biology to carry out closely aligned mechanistic studies using both aging and AD models. It examines the intersection of a molecular mechanism that is broadly relevant to aging (ketone bodies as metabolic signals) with one highly specific to AD (aberrant epilepsy-like network hypersynchrony). It is highly likely to stimulate further progress on AD because the mechanistic framework it generates will directly inform translational studies involving ketone body compounds and ketogenic diets. These data will help establish criteria for designing effective interventions, provide relevant intermediate biomarkers, and permit deeper investigation into the downstream molecular targets most relevant to AD.

项目摘要信号代谢产物是小分子，在细胞能量代谢中具有常规功能，这也是充当信号，以响应不断变化的能量状态来调节科学细胞途径。信号代谢物将营养与衰老联系起来。衰老靶向机制的许多新兴的Geroscience疗法已经出现从对信号代谢产物的发现和理解。酮体β-羟基丁酸（BHB）是一个新的信号代谢物。它是在禁食，饮食限制，运动或碳水化合物限制期间产生的在葡萄糖稀缺时，保持人体的组织为能量提供。我们现在有越来越多的证据表明还可以通过抑制酶来充当信号，直接与蛋白质结合，作为翻译后修饰，和激活受体。通过其信号传导活性，BHB调节基因表达，炎症，对衰老和阿尔茨海默氏病很重要的代谢，感应和其他细胞活性（AD）。我们最近首次展示了刺激内源性产生的生酮饮食（KD） BHB类似于禁食，改善了老化小鼠的生存，并防止与年龄相关的记忆下降。我们也是发现KD改善了HAPPJ20 AD鼠标模型中的记忆，并减少了异常的癫痫样导致记忆力下降的排放。 KD是一种复杂的干预措施，尽管现在正在研究在AD的临床试验中，更好地了解KD的哪些方面最有帮助的有针对性，更有效的疗法。我们已经成功地开发了一种创新的饮食工具集，化学和遗传工具，用于分离KD的各个组件，包括碳水化合物限制，BHB， BHB的能量提供，BHB的细胞信号传导活性。我们将使用这些工具来揭示特定的 BHB改善正常衰老和AD小鼠的记忆的机制（AIM 1），并降低癫痫样 AD小鼠的排出（AIM 2）。我们将表征BHB在蛋白质组学中引起的关键分子变化大脑的景观，包括映射乙酰基组和新的Bhbylome（AIM 3）。该项目将Geroscience和AD的专业知识与BHB生物学的深入了解相结合使用衰老和AD模型进行紧密比对的机械研究。它检查了一种与高度相关的分子机制（酮体作为代谢信号）广泛相关特定于AD（异常癫痫样网络超同步）。很可能会刺激进一步的进展广告，因为它生成的机械框架将直接为涉及酮的翻译研究提供信息身体化合物和生酮饮食。这些数据将有助于建立设计有效干预措施的标准，提供相关的中间生物标志物，并允许对下游分子靶标进行更深入的投资与广告最相关。