mtDNA leakage and STING-dependent microglial innate immune response in Alzheimer's disease
阿尔茨海默病中 mtDNA 渗漏和 STING 依赖性小胶质细胞先天免疫反应
基本信息
- 批准号:10549825
- 负责人:
- 金额:$ 47.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-15 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAffectAlzheimer&aposs DiseaseAmyloid beta-ProteinAnimal Disease ModelsApoptoticAttenuatedBAX geneBiological AssayBrainBrain InjuriesBrain PathologyCellsCognitive deficitsCritical PathwaysCyclic GMPCytosolDNADataDementiaDevelopmentDiffuse Lewy Body DiseaseDiseaseDown SyndromeExtravasationGene ActivationGene Expression ProfileGolgi ApparatusHippocampusImmuneImpaired cognitionInflammation MediatorsInflammatoryInnate Immune ResponseInterferonsLearningLightLinkMediatingMemoryMessenger RNAMicrogliaMitochondriaMitochondrial DNAMorphologyMusMyelogenousNerve DegenerationNeurodegenerative DisordersNeuronsOxidative StressPathologicPathway interactionsPatientsPhagocytosisPhenotypePhosphorylationPilot ProjectsPreventiveProductionRegulationReportingRoleSenile PlaquesShapesSignal TransductionSourceSterilityStimulator of Interferon GenesStressSynapsesTestingVoltage-Dependent Anion ChannelWestern Blottingabeta accumulationabeta depositionaging populationantiviral immunitybehavior testglial activationmitochondrial dysfunctionmitochondrial permeability transition poreneuroinflammationnovelnovel strategiessensortranscriptomicstreatment strategy
项目摘要
PROJECT SUMMARY
Characterized by progressive cognitive decline, Alzheimer's disease (AD) is the most common type of dementia,
primarily affecting the aging population. Inflammatory activation of microglia is an early pathological feature of
Alzheimer’s disease (AD) and contributes to brain damages. However, the underlying mechanisms that mediate
microglial inflammatory activation in Aβ-rich milieus are not completely understood. Stimulator of interferon
genes (STING) is an innate immune adaptor protein that is abundantly expressed by cells of myeloid origin
including microglia. Despite its roles in interferon-based antiviral immunity, recent studies have revealed an
important contribution of STING signaling to inflammatory damages in non-communicable disorders. cyclic GMP-
AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and signals through STING to promote interferon
signaling and production of inflammatory mediators. Cytosolic accumulation of endogenous DNA especially
mitochondrial DNA (mtDNA) fragments constitutes an important source of endogenous “sterile” activator of
cGAS-STING signaling. In our preliminary study on patients and an AD animal model with AD-like
amyloidopathy, we observed increased microglial STING activity, which contributed to early microglial activation
in 5xFAD mice. In addition, microglia from patients and 5xFAD mice demonstrated cytosolic mtDNA
accumulation; and deficiency of cGAS attenuated microglial STING activation in 5xFAD mice, implicating an
association of cytosolic mtDNA sensing by cGAS with STING activation. Finally, our data suggest that microglial
mitochondrial stress in Aβ milieus may contribute to mtDNA instability and leakage into the cytosol. We therefore
hypothesize that microglial STING signaling triggered via cytosolic mtDNA sensing by cGAS contributes to Aβ-
induced microglial activation, culminating in neuroinflammation and neuronal stress in AD. Here, we aim to
establish a link between microglial STING activity and microglial activation in 5xFAD mice. Next, we will
determine the contribution of microglial STING activation to microglial deregulation-associated brain damages
in 5xFAD mice. In addition, we will address the mechanisms that mediate microglial mtDNA release in Aβ-rich
milieus and determine the importance of mtDNA leakage for the activation of microglial cGAS-STING signaling
in Aβ-rich milieus. Taken together, the results from this study will answer important questions about STING in
shaping microglial phenotype, and will suggest a novel mitochondrial mechanism of microglial activation and
new avenues for the treatment of AD.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Heng Du其他文献
Heng Du的其他文献
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{{ truncateString('Heng Du', 18)}}的其他基金
mtDNA leakage and STING-dependent microglial innate immune response in Alzheimer's disease
阿尔茨海默病中 mtDNA 渗漏和 STING 依赖性小胶质细胞先天免疫反应
- 批准号:
10346449 - 财政年份:2022
- 资助金额:
$ 47.49万 - 项目类别:
GHSR1a and Hippocampal Pathology in Alzheimer's Disease
阿尔茨海默病中的 GHSR1a 和海马病理学
- 批准号:
10163763 - 财政年份:2018
- 资助金额:
$ 47.49万 - 项目类别:
GHSR1a and hippocampal pathology in Alzheimer's Disease
阿尔茨海默病中的 GHSR1a 和海马病理学
- 批准号:
9762825 - 财政年份:2018
- 资助金额:
$ 47.49万 - 项目类别:
GHSR1a and Hippocampal Pathology in Alzheimer's Disease
阿尔茨海默病中的 GHSR1a 和海马病理学
- 批准号:
10393665 - 财政年份:2018
- 资助金额:
$ 47.49万 - 项目类别:
GHSR1a and hippocampal pathology in Alzheimer's Disease
阿尔茨海默病中的 GHSR1a 和海马病理学
- 批准号:
9918235 - 财政年份:2018
- 资助金额:
$ 47.49万 - 项目类别:
GHSR1a and Hippocampal Pathology in Alzheimer's Disease
阿尔茨海默病中的 GHSR1a 和海马病理学
- 批准号:
10266217 - 财政年份:2018
- 资助金额:
$ 47.49万 - 项目类别:
Mitochondrial ATP Synthase Dysfunction and Synaptic Stress in Alzheimer's Disease
阿尔茨海默病中的线粒体 ATP 合酶功能障碍和突触应激
- 批准号:
9160954 - 财政年份:2016
- 资助金额:
$ 47.49万 - 项目类别:
Mitochondrial ATP Synthase Dysfunction and Synaptic Stress in Alzheimer's Disease
阿尔茨海默病中的线粒体 ATP 合酶功能障碍和突触应激
- 批准号:
10266216 - 财政年份:2016
- 资助金额:
$ 47.49万 - 项目类别:
Mitochondrial pore and synaptic stress in Alzheimer's disease
阿尔茨海默病中的线粒体孔和突触应激
- 批准号:
8111441 - 财政年份:2011
- 资助金额:
$ 47.49万 - 项目类别:
Mitochondrial pore and synaptic stress in Alzheimer's disease
阿尔茨海默病中的线粒体孔和突触应激
- 批准号:
8264172 - 财政年份:2011
- 资助金额:
$ 47.49万 - 项目类别:
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