Gut barrier function in Alzheimer’s disease
阿尔茨海默病中的肠道屏障功能
基本信息
- 批准号:10614373
- 负责人:
- 金额:$ 73.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-15 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAlzheimer’s disease biomarkerAmyloidAmyloid beta-42Antibody titer measurementAutomobile DrivingBiological AssayBiological MarkersBlood - brain barrier anatomyBrainCerebrospinal FluidChemicalsCirculationClinicalCognitiveCollectionDementiaDerivation procedureDevelopmentDiseaseDisease ProgressionElderlyFRAP1 geneGastrointestinal tract structureGerm-FreeGnotobioticGoalsHomeostasisHumanImmune responseImmune systemImpairmentIndividualInfrastructureInnate Immune ResponseIntestinal permeabilityIntestinesLactuloseLeukocyte L1 Antigen ComplexLinkLipopolysaccharidesLiquid substanceMannitolMeasuresMediatingMethodsMicrobeMicrobiologyMucous body substanceMusNerve DegenerationNeurodegenerative DisordersParticipantPathogenesisPathologyPermeabilityPersonsPlayPositron-Emission TomographyProcessPublishingReportingResearchResourcesRoleSamplingSignal TransductionSodium Dextran SulfateSystemTestingTherapeuticTimeUnited StatesWisconsinWorkage relatedamyloid pathologyblood-brain barrier permeabilizationcohorteffective therapyexperimental studyglial activationgut dysbiosisgut inflammationgut microbesgut microbiomegut microbiotaindexinginflammatory markerintestinal barriermacromoleculemetagenomemicrobialmicrobiome compositionmouse modelneuroimmunologyneuropathologynovel therapeutic interventionparticipant enrollmentprospectivesuccesssystemic inflammatory responsetau Proteinsvirtual
项目摘要
The age-related processes that contribute to Alzheimer's disease (AD) development, particularly in the
prodromal period, are incompletely understood. Age-related reduction in gut microbiome alpha-diversity is
apparent in the majority of older adults, and is suspected of contributing to brain changes, including the
development of neurodegenerative disease. Our team published the first comprehensive report describing
differences in the gut microbiome observed in AD dementia, including reduced diversity in gut microbiota and
altered composition in people with AD dementia compared to age-matched controls. Furthermore, we found that
differentially abundant genera were associated with cerebrospinal fluid biomarkers of AD, even among
individuals who were cognitively unimpaired. Several studies in mouse models of AD indicate that gut microbiota
play a role in the development of AD neuropathology, however to date, the mechanisms underlying these effects
are virtually unknown. Recently it has also become clear that the innate immune response in AD plays a critical
role in mediating the pathology associated with AD; however the interplay between systemic changes and the
innate immune response in AD are not well understood, nor is it known how these factors impact the progression
of AD pathology. Our overarching goal is to determine the extent to which alterations in the composition of gut
microbiome exacerbate and/or accelerate the development of AD pathology. This proposal is based on the
central hypothesis that age-associated gut dysbiosis and inflammation weaken gut barrier function, which in turn
leads to the systemic dissemination of microbial components, driving an immune response and system wide
changes that worsen AD pathology. To test this hypothesis we propose to study well-characterized participants
enrolled in the Wisconsin Alzheimer's Disease Research Center as well as conventional and gnotobiotic
APPPS1 mice, to address the following specific aims: 1. Determine the longitudinal relationship between gut
microbiome (metagenome), gut inflammation and permeability, and the development of AD pathology in
human participants, and 2. Determine the effects of modifying gut permeability on AD pathology in mice.
We expect that alterations in gut microbiome composition and gut permeability exacerbate AD pathology in
humans, and that impairment of intestinal barrier function and increased gut permeability alters brain
homeostasis and exacerbates AD progression in mouse models of AD. Our research group has been working
to determine the role of gut microbiome in the development of AD pathology for the past 5 years, and we are
perfectly poised to address the proposed aims. We will leverage our expertise in clinical AD, neuroimmunology,
and gut microbiology/gnotobiotic mouse models to successfully carry out the proposed project. Completion of
the proposed experiments is expected to lead to the development of novel therapeutic strategies for AD and
related dementias.
与年龄相关的过程,有助于阿尔茨海默病(AD)的发展,特别是在老年人中,
前驱期,不完全理解。与年龄相关的肠道微生物组α多样性减少
在大多数老年人中很明显,并被怀疑有助于大脑的变化,包括
神经退行性疾病的发展。我们的团队发表了第一份综合报告,
在AD痴呆中观察到的肠道微生物组的差异,包括肠道微生物组多样性的减少,
与年龄匹配的对照组相比,AD痴呆患者的组成发生了变化。此外,我们发现,
差异丰富的属与AD的脑脊液生物标志物相关,即使在
没有认知障碍的人。在AD小鼠模型中的几项研究表明,肠道微生物群
在AD神经病理学的发展中起作用,然而迄今为止,这些作用的机制
几乎无人知晓最近也已经清楚,先天免疫应答在AD中起关键作用。
在介导与AD相关的病理学中的作用;然而,系统性变化和
AD中的先天免疫反应尚不清楚,也不知道这些因素如何影响AD的进展。
AD病理学我们的首要目标是确定肠道组成的改变在多大程度上影响了
微生物组加剧和/或加速AD病理学的发展。这项建议是根据
中心假设,年龄相关的肠道生态失调和炎症削弱肠道屏障功能,这反过来又
导致微生物成分的全身传播,驱动免疫反应和系统范围
导致AD病理恶化的变化。为了验证这一假设,我们建议研究具有良好特征的参与者,
参加了威斯康星州阿尔茨海默病研究中心以及传统和gnotobiotic
APPPS 1小鼠,以解决以下具体目的:1.确定肠道之间的纵向关系
微生物组(宏基因组),肠道炎症和渗透性,以及AD病理学的发展,
人类参与者,2。确定改变肠道通透性对小鼠AD病理学的影响。
我们预计肠道微生物组组成和肠道通透性的改变会加重AD病理,
肠屏障功能受损和肠通透性增加会改变大脑
在AD的小鼠模型中,抗AD抗体可维持体内平衡并加剧AD进展。我们的研究小组一直在研究
确定肠道微生物组在过去5年AD病理学发展中的作用,我们正在
完全准备好实现所提出的目标。我们将利用我们在临床AD,神经免疫学,
和肠道微生物学/gnotobiotic小鼠模型,以成功地开展拟议的项目。完成
预期所提出的实验将导致开发新的AD治疗策略,
相关的痴呆症
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
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 - 财政年份:2023
- 资助金额:
$ 73.99万 - 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:
$ 73.99万 - 项目类别:
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:
$ 73.99万 - 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:
$ 73.99万 - 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:
$ 73.99万 - 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:
$ 73.99万 - 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:
$ 73.99万 - 项目类别:
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