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
- 批准号:10739679
- 负责人:
- 金额:$ 75.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAddressAffectAlzheimer like pathologyAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer’s disease biomarkerAmericanAmyloidAntibodiesApoptosisAttenuatedAutopsyBacteriaBehaviorBiological MarkersBone MarrowBrainBrain regionButyratesC-terminalCASP1 geneCaspaseCentral Nervous SystemCessation of lifeCognitionCognitiveCommunitiesDataDementiaDepositionDevelopmentDietDiet ModificationDietary SupplementationDiseaseDisease ProgressionDisease modelElderlyEncephalitisFecesGerm-FreeGliosisGnotobioticHumanHydroxybutyratesIndividualInflammasomeInnate Immune ResponseInnate Immune SystemKetone BodiesKetonesKnowledgeLinkLiquid substanceMacrophageMediatingMemory impairmentMetabolicMetabolismMetagenomicsMicrogliaMusNeurofibrillary TanglesPathogenesisPathologyPersonsPlasmaPlayProteinsPublic HealthReportingResearchRodentRoleSenile PlaquesSupplementationTestingTherapeuticTherapeutic UsesTissuesUnited StatesWisconsinWorkbeta-Hydroxybutyratebrain metabolismbrain tissuecognitive functioncohortdrinking waterfollow-upglial activationgut colonizationgut microbesgut microbiomegut microbiotahuman old age (65+)improvedin vivoketogenesisketogenic dietmicrobiome compositionmouse modelnovelnovel strategiesnovel therapeutic interventionpreventpublic health relevancereceptorrecruitsuccesstargeted treatmenttau Proteinstherapeutic developmenttherapy development
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
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:
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:
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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