Role of TREM2 R47H in Alzheimer's disease using novel CRISPR/Cas9 mouse models
使用新型 CRISPR/Cas9 小鼠模型研究 TREM2 R47H 在阿尔茨海默病中的作用
基本信息
- 批准号:9377477
- 负责人:
- 金额:$ 4.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2019-05-21
- 项目状态:已结题
- 来源:
- 关键词:AddressAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinAmyotrophic Lateral SclerosisApolipoprotein EArginineBiochemicalBiological AssayBone Marrow TransplantationCRISPR/Cas technologyCell CountCell DeathCell SeparationCell SurvivalCell physiologyCellsCellular StructuresChimera organismCodeCognitive deficitsDataDementiaDepositionDevelopmentDiseaseDominant-Negative MutationEconomicsEnzyme-Linked Immunosorbent AssayFlow CytometryFractureFrontotemporal DementiaGenesGenetic ModelsGenetic studyGoalsGrowthHistidineHomeostasisImageImmune TargetingImmunologic ReceptorsIn VitroInfiltrationInflammationInflammatory ResponseInnate Immune SystemKnock-inKnock-in MouseKnock-outLeadLearningLinkMeasuresMemoryMemory impairmentMicrogliaModelingMusMutationMyeloid Cell ActivationMyeloid CellsNerve DegenerationNeuritesNeurodegenerative DisordersNeuronsOdds RatioParkinson DiseasePathogenesisPathologyPatientsPeripheralPhenotypePlayPrevalenceProcessRNARadialRoleSenile PlaquesShort-Term MemorySpottingsTREM2 geneTechnologyTestingTherapeuticTrainingVariantWateramyloid peptidearmbasebehavior testbrain cellbrain tissueexperimental studygenetic linkagegenome editinghyperphosphorylated tauimmunomodulatory therapiesinflammatory markerinsightinterestloss of functionmacrophagemorris water mazemouse modelneuroinflammationneuron lossneurotoxicnovelnovel therapeuticssocialtranscriptome
项目摘要
Project Summary
Alzheimer's disease (AD) is the most common cause of dementia. AD is expected to increase in prevalence in
the coming decades and poses a significant social and economic problem for an aging populace. Recently, a
heterozygous mutation on the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene was shown to
confer one of the highest odds ratios for the development of AD. This mutation was proposed to cause an
arginine to histidine (R47H) mutation resulting in loss of TREM2 function. Understanding the function of this
TREM2 mutation is crucial to informing novel therapeutics to ameliorate AD. TREM2 is expressed on myeloid
cells of the innate immune system, which include peripheral macrophages and resident CNS microglia, and
therefore provide a novel target for immune-modulating therapies to treat AD. However, before therapeutics
can be developed, the function of TREM2 must be determined. We previously found that TREM2 knockout AD
mice had a significant reduction in amyloid plaque burden, neuroinflammation, and a decrease in
hyperphosphorylated tau. We also observed a significantly loss of plaque-associated myeloid cells which were
identified to be infiltrating macrophages. This was an unexpected finding, as TREM2 loss-of-function should
augment AD pathology. This suggests that additional genetic models are needed to study the contribution of
TREM2 to AD.
In order to address this, we generated a novel TREM2 R47H knock in model using CRISPR/Cas9 genome
editing technology. Our preliminary findings show that amyloid plaque number, plaque-associated myeloid cell
number, and myeloid cell activation was significantly reduced. Again, these findings are contrary to the
expected increase in AD risk. Therefore it is crucial to understand how the TREM2 R47H mutation modulates
additional aspects of AD pathology. The goal of the current project is to characterize the myeloid cell
component, amyloid homeostasis, and neurodegeneration in the TREM2 R47H AD model. This proposal will
provide technical training in isolation of primary microglia for in vitro survival assays, flow cytometry to
determine ontogeny of myeloid cells in the brain, and cell sorting to obtain RNA for transcriptome profiling for
myeloid cell phenotype. Additionally, this proposal includes training in quantification of soluble vs. insoluble
amyloid using ELISA and dot spot assays, and confocal imaging to quantify dystrophic neurites,
hyperphosphorylated tau, and neuronal number. Finally, this proposal includes training in the assessment of
deficits in spatial learning and memory using Morris water maze and working memory using radial arm water
maze. The proposed experiments will test the hypothesis that TREM2 R47H may contribute to poor survival of
resident microglia, poor infiltration of peripheral macrophages, or a combination of these processes. Ultimately,
this may result in an increase in neurotoxic soluble amyloid, which may result in neurodegeneration and
observable cognitive deficits. This proposal will contribute significant insight into the function of TREM2 such
that novel therapeutics can be developed to treat of AD.
项目总结
项目成果
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