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： 阿尔茨海默氏病（AD）引起的痴呆症影响着65岁以上的美国人中的八分之一，目前还没有得到很好的治疗。 治疗。虽然治疗发展主要集中在通过抗体方法清除脑淀粉样蛋白，但脑淀粉样蛋白的治疗方法仍然存在。 还已知代谢在疾病中被显著改变。改变代谢状态-例如，通过 生酮饮食可以通过不完全理解的机制改善认知。先前的研究表明， 急性补充代谢产物β-羟基丁酸酯（BHB），这是由此产生的酮体之一 在AD痴呆患者和AD小鼠模型中，然而，在这方面， 影响BHB水平的因素（除饮食外），以及BHB可能发挥作用的具体机制 对大脑的积极影响是未知的。我们的研究团队已经产生了几个重要的线索， 告知影响BHB水平的因素，以及发现BHB通过抑制作用影响AD病理学 小胶质细胞中的炎性小体。虽然以前在生酮饮食研究中未得到充分重视，但肠道微生物组 对BHB水平有显着影响。使用gnotobiotic小鼠，我们提供了BHB脑水平的初步证据， 可以通过精确控制肠道菌群来改变。我们还发现， BHB通过在饮用水中长期直接给药，可显著降低斑块负荷 和5XFAD小鼠中的小胶质细胞增生。此外，在我们对来自威斯康星州ADRC的AD患者的组织的研究中， 在进行尸检的痴呆患者中，我们发现与没有BHB的人相比， 死亡时AD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 疾病进展和解决知识差距，将促进这种代谢物的治疗用途。回答 这些问题具有直接的翻译意义，并有望导致新的策略，以防止或 减缓AD的进程。在这里，我们假设BHB通过抑制AD相关的病理， 通过小胶质细胞中Hcar 2的活化来活化Nlrp 3炎性体。我们将确定的特点， 在淀粉样β斑块的5XFAD小鼠模型中介导BHB对AD病理学影响的炎性体 沉积，确定肠道微生物组通过产丁酸细菌影响BHB水平的程度，以及 最后，利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在多大程度上 使用流体生物标志物，组合物和BHB与AD病理学相关。这里提出的工作将提供 更深入地了解先天免疫系统，肠道微生物和AD代谢之间的相互作用， 产生所需的数据，这些数据将支持新策略的开发，以预防或减缓AD的进程。