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Microglia-specific proteomic mechanisms and biomarkers of neuroinflammation in Alzheimer’s disease

Microglia-specific proteomic mechanisms and biomarkers of neuroinflammation in Alzheimer’s disease
阿尔茨海默病神经炎症的小胶质细胞特异性蛋白质组学机制和生物标志物
批准号:
10179808
负责人:
Srikant Rangaraju
金额:
$111.7万
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
项目状态:
已结题
起止时间:
2021-04-01 至 2023-10-01
关键词:
APP-PS1AdultAgeAgingAlkynesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer’s disease biomarkerAmino AcidsAmyloid beta-ProteinAnimalsAnti-Inflammatory AgentsApolipoprotein EAstrocytesAutopsyAzidesBioinformaticsBiological MarkersBiological ProcessBiologyBrainCell SeparationCellsCerebrospinal FluidCerebrospinal Fluid ProteinsCharacteristicsChemistryCoupledDementiaDependenceDiseaseGeneticGenetic RiskHumanHuman GeneticsImmuneImmunologic MarkersImpaired cognitionInflammasomeInflammationInflammatoryInterventionKnock-in MouseKnowledgeLabelLate Onset Alzheimer DiseaseLeadLipopolysaccharidesLoxP-flanked alleleMass Spectrum AnalysisMediatingMessenger RNAMethionineMethionine-tRNA LigaseMethodologyMethodsMicrogliaModelingMolecularMorphologic artifactsMouse ProteinMusNerve DegenerationNeurodegenerative DisordersNeuroimmunomodulationNeuronsPathogenesisPathologicPathologyPhenotypePositioning AttributeProteinsProteomeProteomicsResolutionRiskRoleSamplingSampling BiasesSynapsesSystems BiologyTamoxifenTestingTranscriptWild Type Mouseabeta accumulationage relatedanalogapolipoprotein E-4beta amyloid pathologybiomarker discoverybrain cellcell typedisorder controlgenetic risk factorimmune checkpointimmunoregulationin vivoinhibitor/antagonistinnovationinsightmouse modelmultidisciplinarymutantneuroinflammationnovelnovel markernovel strategiesnovel therapeutic interventionnovel therapeuticsprotein aggregationprotein biomarkersproteomic signatureselective expressionspecific biomarkerstargeted biomarkertranscriptomicstransgenic model of alzheimer disease

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英文摘要
PROJECT SUMMARY Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by pathological protein aggregation and inflammation in the brain (neuroinflammation). Microglia are the key immune cells of the brain that mediate neuroinflammation. Novel therapeutic strategies and AD biomarkers can be identified if we can define the molecular changes occurring in microglia in AD at the protein level, and not just at the mRNA (transcriptomic) level. Our knowledge about microglial disease mechanisms in AD are mostly shaped by transcriptomic studies although proteins are the enactors of biological processes and the correlation between mRNA and protein is poor. The major barrier to microglial proteomic studies is the dependence on isolation strategies to purify microglia before analyses. Isolation of microglia from brain induces artefacts, yields very little protein and provides highly biased sampling. To overcome this barrier, we will use a novel strategy (ciBONCAT) for microglia-specific proteomic labeling in-vivo. CiBONCAT allows us to label newly synthesized proteins in microglia with an azide tag (azidonorleucine). These azide-tagged proteins can be easily isolated from the brain without need for cell isolation. We have demonstrated the feasibility of using ciBONCAT to label neuronal and astrocytic proteomes in adult mice, and have optimized the in-vivo and mass spectrometry pipelines for proteomics using brain, cerebrospinal fluid (CSF) and other biofluids. This novel strategy, coupled with our extensive expertise in mass spectrometry (proteomics) methods, will allow us to test our central hypothesis that amyloid beta (Aβ) accumulation, APOEε4, and aging independently and synergistically impact proteomic phenotypes of microglia, and that these microglia-mediated mechanisms are reflected in the CSF via immune biomarkers of AD pathology. In Aim 1, we will use ciBONCAT to define microglia-specific protein alterations occurring in AD using two models of progressive amyloid beta pathology (APP-PS1 and 5xFAD). In Aim 2, we will use knock-in mouse models to determine the effect of human APOEε4 and APOEε3 expression on microglial proteins changes and how APOEε4 impacts with Aβ pathology. In Aim 3, we will identify microglia-derived proteins in the cerebrospinal fluid in mouse models of AD pathology to identify novel biomarkers of neuroinflammation that reflect activation or depletion of microglia in the brain in AD mouse models. Through the successful completion of this R01 proposal, we will obtain novel molecular insights into microglia-mediated AD mechanisms and will establish ciBONCAT as a powerful approach to investigate cell type-specific mechanisms of neurodegeneration. Our multidisciplinary expertise in microglial biology and transgenic models of AD pathology (Dr Rangaraju), and quantitative proteomics, systems biology and CSF biomarker discovery (Dr Seyfried), uniquely position us to execute this innovative R01 proposal.
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会议论文
Microglial function of GWAS risk factor BIN1 in Alzheimer's disease pathogenesis and inflammatory signaling
  • 批准号:
    10524611
  • 项目类别:
  • 资助金额:
    $225.05万
  • 财政年份:
    2022
  • 负责人:
    Srikant Rangaraju
  • 依托单位:
Neuron and microglia-specific proteomic signatures of ERK mediated mechanisms of Alzheimer’s disease
  • 批准号:
    10636902
  • 项目类别:
  • 资助金额:
    $106.32万
  • 财政年份:
    2021
  • 负责人:
    Srikant Rangaraju
  • 依托单位:
Neuron and microglia-specific proteomic signatures of ERK mediated mechanisms of Alzheimer’s disease
  • 批准号:
    10374569
  • 项目类别:
  • 资助金额:
    $103.94万
  • 财政年份:
    2021
  • 负责人:
    Srikant Rangaraju
  • 依托单位:
Targeting Kv1.3 potassium channels for neuro-immunomodulation in Alzheimer's Disease
  • 批准号:
    10582681
  • 项目类别:
  • 资助金额:
    $41.99万
  • 财政年份:
    2020
  • 负责人:
    Srikant Rangaraju
  • 依托单位:
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