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

项目总结 信号代谢物是在细胞能量代谢中具有常规功能的小分子，也 作为信号来调节不同的细胞通路，以响应能量状态的变化。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 来自信号代谢物的发现和理解。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期间产生的 当葡萄糖缺乏时，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 也可以作为信号，通过抑制酶，作为翻译后修饰直接与蛋白质结合， 激活感受器。通过其信号活性，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。 我们最近首次展示了生酮饮食(KD)，它刺激内源性生产 类似于禁食的BHB，可提高衰老小鼠的存活率，并防止与年龄相关的记忆力衰退。我们也 发现KD可改善hAPPJ20 AD模型小鼠的记忆，减少异常癫痫样改变 导致记忆力下降的放电。KD是一种复杂的干预措施，尽管目前正在研究中 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导致更好的 有针对性和更有效的治疗方法。我们已经成功地开发了一套创新的饮食， 用于分离KD单个成分的化学和遗传工具，包括限制碳水化合物、BHB、 BHB的能量供应，以及BHB的细胞信号活动。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(目标1)，并减少癫痫发作 阿尔茨海默病小鼠的放电(目标2)。我们将描述BHB在蛋白质组中引起的关键分子变化 脑部图像，包括绘制乙酰组和新的BHBylome(目标3)。 该项目结合了老年学和AD方面的专业知识以及对BHB生物学的深入了解 使用衰老和AD模型进行紧密结合的机制研究。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(异常癫痫样网络超同步)的特异性。它极有可能刺激在以下方面取得进一步进展 因为它产生的机制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研究 与AD最相关的。

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.