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

• 批准号: 10163116
• 负责人: John C Newman
• 金额: $ 75.8万
• 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: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10163116
• 关键词: Acetoacetates; Acetylation; Acute; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' 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; Enzymes; Epigenetic Process; Epilepsy; Esters; Exercise; Fasting; Functional disorder; Gene Expression; Genetic; Geroscience; Glucose; Glutamates; HDAC6 gene; Hippocampus (Brain); Histone Deacetylase Inhibitor; Histones; Individual; Inflammasome; Inflammation; Intervention; Intraperitoneal Injections; Investigation; Ketone Bodies; Ketones; Knock-out; Laboratories; Laboratory mice; Lead; Link; Lipids; Longevity; Macronutrients Nutrition; Mass Spectrum Analysis; Memory; Memory Loss; Memory impairment; Metabolic; Metabolism; Molecular; Molecular Target; Mus; Neurons; Oral; Oxides; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Post-Translational Protein Processing; Prevention; Production; Proteins; Proteome; Proteomics; Science; Signal Transduction; Site; Structure; System; Testing; Time; Tissues; Visuospatial; Wild Type Mouse; Work; age related; aging brain; beta-Hydroxybutyrate; brain dysfunction; brain health; chemical genetics; combinatorial; design; dietary; dietary restriction; effective intervention; effective therapy; enantiomer; feeding; functional decline; gamma-Aminobutyric Acid; human old age (65+); improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; ketogenesis; ketogenic diet; mouse model; neuroprotection; new therapeutic target; normal aging; nutrition; oxidation; prevent; protein B; protein function; receptor; resilience; response; senescence; small molecule; targeted agent; targeted treatment; tau Proteins; tool; translational study

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.

项目概要 信号代谢物是在细胞能量代谢中具有常规功能的小分子， 作为信号来调节不同的细胞途径以响应不断变化的信号代谢物。 许多针对衰老机制的新兴老年科学疗法已经出现。 酮体 β-羟基丁酸 (BHB) 是一种信号代谢物的发现和理解。 它是在禁食、饮食限制、运动或碳水化合物限制期间产生的。 当葡萄糖匮乏时，我们现在有越来越多的证据表明它可以为身体组织提供能量。 还通过抑制酶作为信号发挥作用，直接与蛋白质结合作为翻译后修饰， BHB 通过其信号活动调节基因表达、炎症、 新陈代谢、衰老和其他对衰老和阿尔茨海默病 (AD) 都很重要的细胞活动。 我们最近首次展示了生酮饮食（KD），它可以刺激内源性生产 BHB 与禁食类似，可以提高衰老小鼠的存活率并防止与年龄相关的记忆力下降。 发现 KD 可以改善 hAPPJ20 AD 小鼠模型的记忆力，并减少异常癫痫样症状 导致记忆衰退的放电是一种复杂的干预措施，尽管现在正在研究它。 在 AD 的临床试验中，更好地了解 KD 的哪些方面最有帮助应该会带来更好的结果。 我们已经成功开发了一套创新的饮食疗法， 用于分离 KD 各个成分的化学和遗传工具，包括碳水化合物限制、BHB、 BHB 的能量提供以及 BHB 的细胞信号活动我们将使用这些工具来揭示具体的情况。 BHB 改善正常衰老和 AD 小鼠记忆力的机制（目标 1），并减少癫痫样发作 AD 小鼠中的放电（目标 2）我们将描述 BHB 在蛋白质组中引起的关键分子变化。 大脑景观，包括绘制乙酰基因组和新的 BHBylome 地图（目标 3）。 该项目结合了老年科学和 AD 方面的专业知识以及对 BHB 生物学的深刻理解 使用衰老和 AD 模型进行紧密一致的机制研究，它检查了两者的交叉点。 一种与衰老广泛相关的分子机制（酮体作为代谢信号），具有高度 它很可能刺激 AD（异常癫痫样网络超同步）的进一步进展。 AD 因为它生成的机制框架将直接为涉及酮的转化研究提供信息 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研究 与 AD 最相关。