ß-hydroxybutyrate inhibition of pathology in Alzheimer's disease

项目摘要：。 阿尔茨海默病(AD)导致的痴呆症影响着每8名65岁以上的美国人中的1人，目前情况不佳 治疗过了。虽然治疗开发主要集中在通过抗体方法清除大脑淀粉样蛋白，但大脑 众所周知，这种疾病的新陈代谢也发生了很大的变化。改变代谢状态--例如，通过 生酮饮食--可以通过不完全了解的机制改善认知。此前的研究表明， 急性补充代谢物β-羟丁酸酯(BHb)，它是由此产生的酮体之一 酮体生成可改善AD痴呆患者和AD小鼠模型的认知功能。然而， 除了饮食以外，影响BHB水平的因素，以及BHB可能发挥作用的具体机制 对大脑的积极影响尚不清楚。我们的研究团队已经产生了几条重要的线索， 告知影响BHB水平的因素，并发现BHB通过抑制作用影响AD病理 小胶质细胞中的炎性小体。虽然以前在生酮饮食的研究中被低估，但肠道微生物组 对BHB水平有重大影响。利用灵知生菌小鼠，我们提供了BHB脑水平的初步证据 可以通过对肠道微生物区系的精确操纵来改变。我们还发现，改变土壤中的 长期直接饮用BHB可显著减轻菌斑负担 和5XFAD小鼠的小胶质细胞增多。此外，在我们对威斯康星州ADRC AD患者组织的研究中 来尸检的痴呆症患者，我们发现与没有进行尸检的人相比，大脑中的BHb水平较低 死亡时的AD痴呆。在拟议的研究中，我们将跟进这些发现，以确定BHB是如何调节的 疾病进展和解决知识差距，这将促进这种代谢物的治疗使用。接听 这些问题具有直接的翻译意义，并有望导致防止或 减缓AD的进程。在这里，我们假设BHB通过抑制AD相关的病理来保护AD NLRP3通过激活小胶质细胞中的Hcar2来激活炎性小体。我们将确定 5XFAD小鼠淀粉样蛋白β斑块模型中炎症小体介导黄连对AD病理的影响 沉积，确定肠道微生物群通过丁酸盐产生菌影响BHB水平的程度，以及 最后，使用人类元基因组和生物标记物数据，我们将确定肠道微生物组的程度 使用流体生物标记物，成分和BHB与AD病理有关。这里提出的工作将提供 对阿尔茨海默病先天免疫系统、肠道微生物和新陈代谢之间的相互作用有了更深入的了解， 生成所需的数据，以支持开发新的策略来预防或减缓AD的进程。

Project Summary: . Dementia due to Alzheimer’s disease (AD) affects 1 in 8 Americans over the age of 65, and is currently not well treated. While therapeutic development has largely focused on clearing brain amyloid via antibody approaches, brain metabolism is also known to be substantially altered in the disease. Altering the metabolic state—for example, via ketogenic diet—can improve cognition through incompletely understood mechanisms. Previous studies indicate that acute supplementation with the metabolite β-hydroxybutyrate (BHB), one of the ketone bodies produced as a result of ketogenesis, improves cognitive function both in people with AD dementia and in mouse models of AD. However, the factors—apart from diet—that impact BHB levels, as well as the specific mechanisms by which BHB may exert positive impacts on the brain are unknown. Our research team has generated several important leads that better inform the factors that impact BHB levels, as well as discovering that BHB impacts AD pathology through inhibition of the inflammasome in microglia. While previously underappreciated in studies of ketogenic diet, gut microbiome has a significant impact on BHB levels. Using gnotobiotic mice, we provide preliminary evidence brain levels of BHB can be altered by precise manipulation of the gut microbiota. We have also found that modifying the abundance of BHB through long-term direct administration in the drinking water results in remarkably diminished plaque burden and microgliosis in 5XFAD mice. Further, in our studies of tissue from individuals in the Wisconsin ADRC with AD dementia who came to autopsy, we found that brain levels of BHB levels were lower compared to individuals without AD dementia at death. In the proposed study, we will follow up these findings to determine how BHB modulates disease progression and address knowledge gaps that would facilitate therapeutic use of this metabolite. Answering these questions has immediate translational implications and is expected to lead to novel strategies to prevent or slow the course of AD. Here, we hypothesize that BHB protects against AD-associated pathology by inhibiting Nlrp3 inflammasome activation through activation of Hcar2 in microglia. We will determine the features of the inflammasome that mediate the effects of BHB on AD pathology in the 5XFAD mouse models of amyloid β plaque deposition, determine the extent to which gut microbiome impacts BHB levels via butyrate producing bacteria, and finally, using human metagenomic and biomarker data we will determine the extent to which gut microbiome composition and BHB are associated with AD pathology using fluid biomarkers. The work proposed here will provide a deeper understanding of the interplay between the innate immune system, gut microbes, and metabolism in AD, generating the needed data that will support the development of novel strategies to prevent or slow the course of AD.