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

项目摘要 信号代谢物是在细胞能量代谢中具有常规功能的小分子， 作为信号调节不同的细胞通路以响应变化的能量状态。信号代谢物 将营养与衰老联系起来。许多针对衰老机制的新兴老年科学疗法已经出现， 从发现和理解信号代谢物。酮体β-羟基丁酸酯（BHB）是一种 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时产生的 在葡萄糖缺乏的时候保持身体组织的能量供应。我们现在有越来越多的证据表明 也作为信号，通过抑制酶，直接结合蛋白质作为翻译后修饰， 和激活受体。通过其信号传导活动，BHB调节基因表达，炎症， 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。 我们最近首次表明，生酮饮食（KD），刺激内源性生产 BHB类似于禁食，可提高衰老小鼠的存活率，并防止与年龄相关的记忆力下降。我们也 发现KD改善了hAPPJ20 AD小鼠模型的记忆，并减少了异常的癫痫样发作。 导致记忆衰退的放电KD是一种复杂的干预措施，尽管目前正在研究 在AD的临床试验中，更好地了解KD的哪些方面最有帮助， 更有针对性和更有效的治疗。我们已经成功地开发了一套创新的饮食工具， 化学和遗传工具来分离KD的各个组分，包括碳水化合物限制，BHB， BHB的能量供应和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小鼠记忆的机制（目的1）， 在AD小鼠中的放电（目的2）。我们将描述BHB在蛋白质组中引起的关键分子变化， 大脑的景观，包括绘制乙酰基组和新的BHB基因组（目标3）。 该项目结合了老年科学和AD的专业知识，并深入了解BHB生物学 使用老化和AD模型进行密切一致的机制研究。它考察了 一种与衰老广泛相关的分子机制（酮体作为代谢信号）， AD（aberrant epilepsy like network hypersynchrony）它极有可能刺激在以下方面取得进一步进展： AD，因为它产生的机制框架将直接告知涉及酮的转化研究 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点进行更深入的研究 与AD最相关

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.