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

基本信息

项目摘要

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.
项目总结:。

项目成果

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Barbara Brigitta Bendlin其他文献

Barbara Brigitta Bendlin的其他文献

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{{ truncateString('Barbara Brigitta Bendlin', 18)}}的其他基金

Administrative Supplement to Establish National Exposome Alzheimer's Disease and Related Dementias (ADRD) Infrastructure (Expo-AD)
建立国家阿尔茨海默氏病和相关痴呆症 (ADRD) 基础设施 (Expo-AD) 的行政补充
  • 批准号:
    10658250
  • 财政年份:
    2021
  • 资助金额:
    $ 75.24万
  • 项目类别:
Gut barrier function in Alzheimer’s disease
阿尔茨海默病中的肠道屏障功能
  • 批准号:
    10614373
  • 财政年份:
    2021
  • 资助金额:
    $ 75.24万
  • 项目类别:
The Neighborhoods Study: Contextual Disadvantage and Alzheimer’s Disease and Related Dementias (ADRD)
社区研究:环境劣势与阿尔茨海默病及相关痴呆症 (ADRD)
  • 批准号:
    10803585
  • 财政年份:
    2021
  • 资助金额:
    $ 75.24万
  • 项目类别:
The Neighborhoods Study: Contextual Disadvantage and Alzheimer’s Disease and Related Dementias (ADRD)
社区研究:环境劣势与阿尔茨海默病及相关痴呆症 (ADRD)
  • 批准号:
    10361428
  • 财政年份:
    2021
  • 资助金额:
    $ 75.24万
  • 项目类别:
Gut barrier function in Alzheimer’s disease
阿尔茨海默病中的肠道屏障功能
  • 批准号:
    10350685
  • 财政年份:
    2021
  • 资助金额:
    $ 75.24万
  • 项目类别:
The Neighborhoods Study: Contextual Disadvantage and Alzheimer’s Disease and Related Dementias (ADRD)
社区研究:环境劣势与阿尔茨海默病及相关痴呆症 (ADRD)
  • 批准号:
    10580795
  • 财政年份:
    2021
  • 资助金额:
    $ 75.24万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10385840
  • 财政年份:
    2019
  • 资助金额:
    $ 75.24万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10601075
  • 财政年份:
    2019
  • 资助金额:
    $ 75.24万
  • 项目类别:
SV2A PET imaging in Alzheimer's Disease
SV2A PET 成像在阿尔茨海默病中的应用
  • 批准号:
    9919489
  • 财政年份:
    2018
  • 资助金额:
    $ 75.24万
  • 项目类别:
SV2A PET imaging in Alzheimer's Disease
SV2A PET 成像在阿尔茨海默病中的应用
  • 批准号:
    10403978
  • 财政年份:
    2018
  • 资助金额:
    $ 75.24万
  • 项目类别:

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