Dynamic immune cell landscape in late-onset Alzheimer's disease: role of ApoE-mediated microglial lipid metabolism
晚发性阿尔茨海默病的动态免疫细胞景观:ApoE 介导的小胶质细胞脂质代谢的作用
基本信息
- 批准号:10370588
- 负责人:
- 金额:$ 45.1万
- 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:2022-03-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAntibodiesApolipoprotein EBindingBiochemicalBiological AssayBloodBlood VesselsBrainCell LineageCell Surface ProteinsCell membraneCell physiologyCellsCholesterolChronicCognitive deficitsComplexDementiaDevelopmentDietary FatsDimensionsDiseaseDisease ProgressionE proteinElderlyEnvironmental Risk FactorExhibitsGene ActivationGenesGeneticGenetic RiskGenetic TranscriptionGenotypeHealthHemostatic functionHeterogeneityHomeostasisHumanImmuneImmunityImpaired cognitionIndividualInfiltrationInflammationInflammation MediatorsInflammatoryInvestigationKnock-in MouseKnowledgeLate Onset Alzheimer DiseaseLinkLipidsMeasurementMeasuresMediatingMembrane MicrodomainsMembrane ProteinsMetabolismMicrogliaMolecularMolecular ProfilingMusMyelogenousNerve DegenerationObesityOligonucleotidesPathogenesisPathway interactionsPeripheralPhenotypePhospholipidsPlayPopulationProductionProtein IsoformsProteinsRNAResolutionRiskRoleSenile PlaquesSignal PathwaySphingomyelinsT-LymphocyteTLR2 geneTREM2 geneTestingTissuesTriglyceridesTumor-infiltrating immune cellsUnited StatesUp-RegulationWorkapolipoprotein E-3apolipoprotein E-4combatcytokinediet-induced obesityfatty acid metabolismgene environment interactiongenetic associationgenetic varianthigh riskimmune functionindividualized medicineinflammatory milieuinnovationinsightlifestyle interventionlipid metabolismlipidomelipidomicsmRNA sequencingmacrophagemiddle agemonocytemultimodalityneuroinflammationneurotoxicitynovelnovel therapeutic interventionobese personparticlepreventrecruitsingle-cell RNA sequencingtherapeutically effectivetranscriptometranscriptomics
项目摘要
Project Summary
Alzheimer's disease (AD) is the leading cause of dementia in older adults and affects over 5 million individuals
in the United States alone. The more common form of AD, late-onset, is a multifactorial disorder in which ApoE4
is the most potent genetic risk. The ApoE4 isoform is also linked to midlife obesity which can cause cognitive
decline in older adults. Obesity is a condition of chronic inflammation characterized by activated immune cells
and increased inflammatory mediators in the blood. Recently, through genetic association studies, microglia and
other myeloid origin immune cells have emerged as crucial players in AD pathogenesis. Single-cell RNA
sequencing analysis in mouse and human AD brains has identified a distinct subset associated with amyloid
plaques and the upregulation of ApoE in microglia. Therefore, further investigation of microglia and other immune
cells is needed to understand how these cells are affected by ApoE4 isoform and obesity contributing to late-
onset AD progression. Our objective in this R21 project is to explore the gene-environment interactions between
ApoE4 and obesity in regulating phenotypic plasticity of microglia and peripheral immune cells. This project aims
to identify molecular pathways that could restore healthy immune function to treat late-onset AD. Our Specific
Aims are to (1) Assess dynamic changes of brain immune cell populations influenced by ApoE4 and diet-induced
obesity in human ApoE isoform knock-in mice; (2) Identify altered lipid metabolism in ApoE4 microglia that
modulates the phenotypic plasticity. The successful completion of this project will reveal the multifaceted roles
of ApoE4 in modulating immunometabolism. Moreover, it will provide a strong rationale for lifestyle interventions
or individualized therapeutic strategies for late-onset AD in ApoE4 carriers.
项目摘要
阿尔茨海默病(AD)是老年人痴呆症的主要原因,影响超过500万人
仅在美国。AD的更常见形式,迟发性,是一种多因素疾病,其中ApoE 4
是最大的遗传风险ApoE 4亚型也与中年肥胖有关,中年肥胖可导致认知功能障碍。
老年人下降。肥胖是一种慢性炎症状态,其特征是免疫细胞被激活
以及血液中炎症介质的增加。最近,通过遗传关联研究,小胶质细胞和
其它髓源性免疫细胞已成为AD发病机制中的关键参与者。单细胞RNA
对小鼠和人类AD大脑的测序分析已经确定了与淀粉样蛋白相关的一个独特的子集
斑块和小胶质细胞中ApoE的上调。因此,进一步研究小胶质细胞和其他免疫
需要了解这些细胞是如何受到ApoE 4同种型和肥胖的影响,从而导致晚期-
AD进展发作。我们在这个R21项目中的目标是探索基因与环境的相互作用,
ApoE 4与肥胖对小胶质细胞和外周免疫细胞表型可塑性的调节该项目旨在
以确定可以恢复健康免疫功能的分子途径来治疗迟发性AD。我们的具体
目的是(1)评估ApoE 4和饮食诱导的脑免疫细胞群的动态变化
人ApoE同种型基因敲入小鼠中的肥胖;(2)鉴定ApoE 4小胶质细胞中改变的脂质代谢,
调节表型可塑性。该项目的成功完成将揭示多方面的作用
ApoE 4在调节免疫代谢中的作用。此外,它将为生活方式干预提供强有力的理由
或针对ApoE 4携带者中迟发性AD的个体化治疗策略。
项目成果
期刊论文数量(1)
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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