ß-hydroxybutyrate inhibition of pathology in Alzheimer's disease

α-羟基丁酸对阿尔茨海默病病理学的抑制作用

• 批准号: 10739679
• 负责人: Barbara Brigitta Bendlin
• 金额: $ 75.24万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739679
• 关键词: Acute; Address; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; American; Amyloid; Antibodies; Apoptosis; Attenuated; Autopsy; Bacteria; Behavior; Biological Markers; Bone Marrow; Brain; Brain region; Butyrates; C-terminal; CASP1 gene; Caspase; Central Nervous System; Cessation of life; Cognition; Cognitive; Communities; Data; Dementia; Deposition; Development; Diet; Diet Modification; Dietary Supplementation; Disease; Disease Progression; Disease model; Elderly; Encephalitis; Feces; Germ-Free; Gliosis; Gnotobiotic; Human; Hydroxybutyrates; Individual; Inflammasome; Innate Immune Response; Innate Immune System; Ketone Bodies; Ketones; Knowledge; Link; Liquid substance; Macrophage; Mediating; Memory impairment; Metabolic; Metabolism; Metagenomics; Microglia; Mus; Neurofibrillary Tangles; Pathogenesis; Pathology; Persons; Plasma; Play; Proteins; Public Health; Reporting; Research; Rodent; Role; Senile Plaques; Supplementation; Testing; Therapeutic; Therapeutic Uses; Tissues; United States; Wisconsin; Work; beta-Hydroxybutyrate; brain metabolism; brain tissue; cognitive function; cohort; drinking water; follow-up; glial activation; gut colonization; gut microbes; gut microbiome; gut microbiota; human old age (65+); improved; in vivo; ketogenesis; ketogenic diet; microbiome composition; mouse model; novel; novel strategies; novel therapeutic intervention; prevent; public health relevance; receptor; recruit; success; targeted treatment; tau Proteins; therapeutic development; therapy development

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.

项目概要： . 65 岁以上的美国人中，八分之一的人患有阿尔茨海默氏病 (AD) 造成的痴呆症，目前状况不佳 治疗。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 已知代谢在疾病中也发生显着改变。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提高认知能力。先前的研究表明 急性补充代谢物 β-羟基丁酸 (BHB)，这是由此产生的酮体之一 生酮作用可改善 AD 痴呆症患者和 AD 小鼠模型的认知功能。然而， 除饮食外，影响 BHB 水平的因素，以及 BHB 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一些重要的线索，可以更好地 了解影响 BHB 水平的因素，并发现 BHB 通过抑制影响 AD 病理 小胶质细胞中的炎症小体。虽然以前在生酮饮食研究中并未得到充分重视，但肠道微生物组 对 BHB 水平有显着影响。使用无菌小鼠，我们提供了 BHB 大脑水平的初步证据 可以通过精确控制肠道微生物群来改变。我们还发现，改变丰度 通过长期直接在饮用水中施用 BHB 可显着减少菌斑负担 和 5XFAD 小鼠的小胶质细胞增生。此外，我们对威斯康星州 ADRC 患有 AD 患者的组织进行了研究 进行尸检的痴呆症患者中，我们发现与没有痴呆症的个体相比，大脑中 BHB 水平较低 AD 死亡时痴呆。在拟议的研究中，我们将跟踪这些发现以确定 BHB 如何调节 疾病进展并解决知识差距，从而促进这种代谢物的治疗用途。正在接听 这些问题具有直接的转化意义，预计将导致新的战略来预防或 减缓 AD 的进程。在这里，我们假设 BHB 通过抑制 通过激活小胶质细胞中的 Hcar2 来激活 Nlrp3 炎症小体。我们将确定其特征 炎症小体介导 BHB 对 5XFAD β 淀粉样斑块小鼠模型中 AD 病理学的影响 沉积，确定肠道微生物群通过产生丁酸盐的细菌影响 BHB 水平的程度，以及 最后，使用人类宏基因组和生物标志物数据，我们将确定肠道微生物组的程度 使用液体生物标志物，成分和 BHB 与 AD 病理学相关。这里提出的工作将提供 更深入地了解 AD 中先天免疫系统、肠道微生物和新陈代谢之间的相互作用， 生成所需的数据，支持制定预防或减缓 AD 进程的新策略。