Microglial heparan sulfate in the modulation of APOE function and neurodegeneration
小胶质细胞硫酸乙酰肝素调节 APOE 功能和神经退行性变
基本信息
- 批准号:10555329
- 负责人:
- 金额:$ 58.1万
- 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:2022-02-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:ATP binding cassette transporter 1AblationAffinityAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloid depositionAnimalsApolipoprotein EAttentionBehavioralBindingBinding ProteinsBrainBrain PathologyCell surfaceChargeCholesterolCodeCore ProteinDataDementiaDevelopmentExcisionExhibitsExtracellular MatrixGenesGeneticGenetic PolymorphismGenetic RiskGenomicsGoalsHeparan Sulfate ProteoglycanHeparinHeparitin SulfateHeparitin sulfotransferaseHumanHuman GeneticsImmunomodulatorsImpaired cognitionIn VitroLate Onset Alzheimer DiseaseLigandsLinkLipidsMaintenanceMediatingMedicalMicrogliaMolecularMusMutant Strains MiceMutationNerve DegenerationNeuronsPathway interactionsPhenotypePlayPolysaccharidesProcessProtein IsoformsProteinsRecurrent diseaseRegulationRelative RisksReportingResearchResearch PriorityResistanceRiskRisk FactorsRoleSenile PlaquesSeriesSignal TransductionSulfateSurfaceSynapsesTREM2 geneVariantWomanapolipoprotein E-3apolipoprotein E-4cationic antimicrobial protein CAP 37cholesterol transportersexperimental studyfunctional genomicsgenetic associationgenetic risk factorgenomic dataglial activationglycosylationimmunoregulationin vivoinsightmouse modelneuroinflammationnovelpresenilin-1receptorresponsesugartau Proteinstherapeutic target
项目摘要
Heparan sulfate (HS), a sulfated glycan expressed at the cell surface and in extracellular matrix, has long
attracted attention as a putative factor involved in Alzheimer's disease (AD), based on circumstantial
evidence from in vitro and clinicopathological studies. Nevertheless, the functional significance of HS in
AD, especially in the late-onset type (LOAD) that comprises more than 90% of AD cases, is elusive. Recent
human genomic studies implicate ApoE and microglia as dominant contributors to neurodegeneration in
LOAD. The APOE gene is the strongest known genetic risk factor for LOAD. Accumulating data indicate
that ApoE proteins exert immunomodulatory effects on microglia, and that this function of ApoE is at least
partly mediated by the TREM2 receptor, another AD risk factor that is expressed by microglia. Among the
three human APOE alleles, the APOE4 allele confers an increased risk for LOAD, while the APOE2 allele
confers a decreased risk relative to the more common APOE3 allele. The molecular basis of these allele-
specific risk variations is one of the key unanswered issues in AD research. In this context, it is interesting
to note that ApoE proteins bind HS in an isoform-specific manner — ApoE4 exhibits 2- to 3-fold greater
affinity for HS than ApoE2 and ApoE3, thus apparently correlating with their relative AD risks. Furthermore,
a recent report regarding the unique case of a Columbian woman, who carries a highly detrimental
PSEN1E280A mutation, suggests that her APOE3 "Christchurch" mutation, which abolishes the affinity of
ApoE3 for HS, confers strong protection against neurodegeneration and cognitive impairment. Also
suggesting the functional involvement of HS in LOAD are recurrent reports of genetic association of HS
sulfotransferase genes with LOAD. In a series of preliminary studies, we have obtained multiple pieces of
evidence suggesting that the strong interaction of HS with ApoE4, relative to its interactions with ApoE2
and ApoE3, is the key underlying mechanism by which ApoE4 exerts a detrimental effect on the brain.
Significantly, we have found that haploinsufficient reduction in HS expression leads to the mitigation of
synapse loss and microglial activation in the PS19 TauP310S mouse model. We hypothesize that HS plays
a critical role in mediating the ApoE4 effect on microglial response and function, and that the detrimental
effect of the APOE4 allele is mainly due to its stronger interaction with the 3-O sulfate-rich HS species
expressed in microglia. We will: (1) determine the role of HS in ApoE-TREM2 interaction and signaling in
microglia; (2) determine the role of microglial HS in ApoE/ABCA1-mediated cholesterol efflux; and (3)
examine in vivo effects of microglial HS on brain pathology and function in AD mouse models. This
research will provide entirely novel insights into the role of HS in microglia, and moreover, into long-term
questions regarding the isoform-specific risk of APOE variants. Successful completion of this project will
reveal the ApoE4-HS interaction as a promising therapeutic target for reducing AD risk in APOE4 carriers.
硫酸肝素(HS)是一种在细胞表面和细胞外基质中表达的硫酸化聚糖
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('YU YAMAGUCHI', 18)}}的其他基金
Microglial heparan sulfate in the modulation of APOE function and neurodegeneration
小胶质细胞硫酸乙酰肝素调节 APOE 功能和神经退行性变
- 批准号:
10370905 - 财政年份:2022
- 资助金额:
$ 58.1万 - 项目类别:
Heparan sulfate in neurophysiology and neurological disorders
硫酸乙酰肝素在神经生理学和神经系统疾病中的作用
- 批准号:
8965407 - 财政年份:2015
- 资助金额:
$ 58.1万 - 项目类别:
Heparan sulfate in neurophysiology and neurological disorders
硫酸乙酰肝素在神经生理学和神经系统疾病中的作用
- 批准号:
9105755 - 财政年份:2015
- 资助金额:
$ 58.1万 - 项目类别:
Genetic dissection of the role of chondroitin sulfate in cartilage
硫酸软骨素在软骨中作用的基因解析
- 批准号:
8440194 - 财政年份:2012
- 资助金额:
$ 58.1万 - 项目类别:
Genetic dissection of the role of chondroitin sulfate in cartilage
硫酸软骨素在软骨中作用的基因剖析
- 批准号:
8716529 - 财政年份:2012
- 资助金额:
$ 58.1万 - 项目类别:
Genetic dissection of the role of chondroitin sulfate in cartilage
硫酸软骨素在软骨中作用的基因解析
- 批准号:
8543628 - 财政年份:2012
- 资助金额:
$ 58.1万 - 项目类别:
Genetic dissection of the role of chondroitin sulfate in cartilage
硫酸软骨素在软骨中作用的基因剖析
- 批准号:
8898723 - 财政年份:2012
- 资助金额:
$ 58.1万 - 项目类别:
Heparan Sulfate in Schwann Cell Development and Myelination
硫酸乙酰肝素在雪旺细胞发育和髓鞘形成中的作用
- 批准号:
8185308 - 财政年份:2010
- 资助金额:
$ 58.1万 - 项目类别:
Heparan Sulfate in Skeletal Development and Diseases
硫酸乙酰肝素在骨骼发育和疾病中的作用
- 批准号:
7812498 - 财政年份:2009
- 资助金额:
$ 58.1万 - 项目类别:
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