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.

项目摘要：。 由于阿尔茨海默氏病（AD）引起的痴呆症影响了65岁以上8个美国人，目前还不良好 治疗。虽然治疗开发主要集中于通过抗体方法清除大脑淀粉样蛋白，但大脑 已知新陈代谢在该疾病中发生了重大改变。改变代谢状态，例如， 生酮饮食 - 可以通过不完全理解机制来改善认知。先前的研究表明 用代谢物β-羟基丁酸（BHB）的急性补充，结果是产生的酮体之一 酮症发生，可以提高AD痴呆症患者和AD小鼠模型中的认知功能。然而， 这些因素（从饮食中出发）会影响BHB水平，以及BHB可以执行的特定机制 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个重要的领导者 告知影响BHB水平的因素，并发现BHB通过抑制会影响AD病理 小胶质细胞中的炎性体。虽然先前在生酮饮食研究中被低估了，但肠道微生物组 对BHB水平有重大影响。使用gnotobiotic小鼠，我们提供了BHB的初步证据大脑水平 可以通过精确操纵肠道菌群来改变。我们还发现，修改抽象 BHB通过长期直接给药的饮用水导致斑块伯嫩大幅减少 5xFAD小鼠的小胶质细胞增多症。此外，在我们对威斯康星州ADRC中个人组织的组织中 开始进行尸检的痴呆症，我们发现BHB水平的大脑水平与没有人相比 死亡时痴呆症。在拟议的研究中，我们将跟进这些发现，以确定BHB如何调节 疾病的进展和解决知识差距，这将有助于治疗这种代谢产物。回答 这些问题具有直接的翻译意义，预计将导致预防或 减慢广告的过程。在这里，我们假设BHB通过抑制来预防与AD相关的病理 通过小胶质细胞中HCAR2激活的NLRP3炎性体激活。我们将确定 在淀粉样蛋白β斑块的5xFAD小鼠模型中介导BHB对AD病理的影响的炎性体 沉积，确定肠道微生物组在多大程度上通过丁酸酯产生细菌影响BHB水平，而 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 组成和BHB使用流体生物标志物与AD病理相关。这里提出的工作将提供 对AD中的先天免疫系统，肠道微生物和代谢之间的相互作用有更深入的了解， 生成所需的数据，这些数据将支持开发新的策略，以防止或减慢AD的过程。