TREM2-mediated microglial dynamic function in Alzheimer disease
TREM2 介导的阿尔茨海默病小胶质细胞动态功能
基本信息
- 批准号:10552627
- 负责人:
- 金额:$ 74.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAbeta clearanceAddressAffectAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinApolipoprotein EBehaviorBiochemicalBiological ModelsBrainCRISPR/Cas technologyCell LineCell modelCellsCerebrumCognitiveDementiaDepositionDevelopmentDiseaseDisease ProgressionElectrophysiology (science)EtiologyFutureGene DeliveryGenesGoalsHumanImageImmuneImmune responseIn VitroInflammatory ResponseInjuryKnock-inKnock-outKnowledgeMediatingMessenger RNAMetabolismMethodsMicrodialysisMicrogliaModelingMolecularMolecular ProfilingMolecular TargetMorphologyMusMutationNerve DegenerationNeuronsOrganoidsPathogenesisPathogenicityPathologicPathologyPathway interactionsPhagocytosisPopulationProcessRNA SplicingRoleSenile PlaquesSocietiesSynapsesSystemTREM2 geneTauopathiesTechniquesTechnologyTestingToxic effectValidationVariantabeta depositionabeta toxicityaging brainamyloid formationamyloid pathologycell typedensitygenetic risk factorgenomic locushistopathological examinationhuman modelhuman old age (65+)in vivoin vivo Modelinduced pluripotent stem cellinnovationloss of functionmiddle agemouse modelnovelpharmacologicrare variantrisk variantsingle-cell RNA sequencingstem cell modeltau Proteinstranscriptome sequencingtreatment strategytwo photon microscopytwo-photon
项目摘要
PROJECT SUMMARY
The major goal of this proposal is to address the dynamic role of TREM2-mediated microglial function in
brain aging and during different stages of the pathological development of Alzheimer’s disease (AD). TREM2 is
a microglial specific gene with several of its rare variants associated with AD risk. Despite some progress, the
molecular pathobiology of TREM2 in particular the TREM2-R47H risk variant is still not clear. Studies
examining the effects of loss of TREM2 function in mouse models support inconsistent conclusions; with
TREM2 deficiency either reduces or enhances amyloid or tau pathology and associated toxicity depending on
the stage of the pathological development or the specific mouse models. As such, TREM2-mediated microglial
function likely has dynamic effects on amyloid and tau pathologies depending on pathological stages
throughout AD progression. Further complicating the challenge of studying the impact of TREM2-R47H variant,
a recent study revealed that introducing the R47H mutation into the mouse Trem2 gene locus leads to aberrant
splicing and instability of its mRNA. To fill these gaps in knowledge and the lack of appropriate model systems,
we have generated novel cell type-specific and inducible mouse models expressing human TREM2 or TREM2-
R47H in microglia. To address human relevance and molecular mechanisms, we have also generated human
induced pluripotent stem cell (iPSC) lines carrying TREM2 or TREM2-R47H. Thus, the major goal of this
proposal is to examine the dynamic effects of human TREM2 and TREM2-R47H on microglial and neuronal
functions in aging and AD; while in the process defines the underlying molecular pathways by targeted and
non-targeted approaches. We hypothesize that TREM2-mediated microglial function is protective against the
development of AD pathologies but can be detrimental when such pathologies are associated with synaptic
loss and neurodegeneration. We also hypothesize that TREM2-R47H represents a loss-of-function in particular
in microglia-mediated protection against AD-related pathways. We will test our hypothesis through three aims.
In Aim 1, we plan to analyze the effects of TREM2 or TREM2-R47H upon injury paradigms and during aging in
the absence of AD pathology. In Aim 2, we will examine the effects of TREM2 or TREM2-R47H on the
metabolism, deposition, and toxicity of Aβ and tau at different stages of pathological development. In Aim 3, we
plan to identify and validate the molecular pathways associated with TREM2 and TREM2-R47H using iPSC-
derived microglia-like cells with or without integration into cerebral organoids. This innovative proposal will take
advantage of our existing conditional mouse models and iPSC-derived cellular models combined with state-of-
the-art technologies including in vivo microdialysis, two-photon microscopy and molecular profiling by single
cell RNA-Seq. These efforts should collectively help to understand how TREM2 modulates microglial dynamic
roles in aging and AD pathogenesis and how we can target these pathways to treat AD.
项目总结
项目成果
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