ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease
ApoE4 和 C/EBP:在阿尔茨海默病中相互调节
基本信息
- 批准号:10533321
- 负责人:
- 金额:$ 46.49万
- 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 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:27-hydroxycholesterol3xTg-AD mouseAbeta clearanceAge of OnsetAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinAnimal ModelApolipoprotein EApplications GrantsAstrocytesBackBindingBinding ProteinsBiochemicalBiological AssayBrainCCAAT-Enhancer-Binding ProteinsCardiovascular DiseasesCellsCentral Nervous SystemCholesterolCholesterol HomeostasisComplexConsensusDepositionDisease ProgressionEventFamilyFatty acid glycerol estersFeedsFutureGene FamilyGenetic TranscriptionGoalsHumanInflammatoryInterleukin-6Knock-outKnowledgeLDL-Receptor Related Protein 1LiverLow Density Lipoprotein ReceptorMacrophageMediatingMessenger RNAMolecularMusNeurofibrillary TanglesNeurogliaNeuronsOnset of illnessPathogenesisPathologicPathologyPathway interactionsPeptide HydrolasesPeripheralPersonsPlayProductionProtein IsoformsProteinsReportingRiskRoleSenile PlaquesTestingTherapeutic InterventionTissuesTransgenic MiceUp-RegulationViral VectorYY1 Transcription Factoradipocyte differentiationage relatedapolipoprotein E-3apolipoprotein E-4asparaginylendopeptidasecytokinefactor Cgenetic risk factorinnovationinsightlipid metabolismmembermouse modelneurofibrillary tangle formationoverexpressionpromoterreceptorsecretasespatiotemporaltau Proteinstau expressiontau mutationtranscription factor
项目摘要
ApoE4 is the major genetic risk factor for Alzheimer's disease (AD) pathogenesis. In the central nervous
system (CNS), ApoE is mainly produced by glia and astrocytes and transports cholesterol to neurons via ApoE
receptors, which are members of the low density lipoprotein receptor (LDLR) gene family. ApoE isoform-
specific interactions with Aβ, namely ApoE/Aβ complex, modulates Aβ levels and is implicated in Aβ
clearance. C/EBPβ is an inflammatory cytokines-regulated transcription factor that can be activated by Aβ as
well. Interestingly, we have recently reported that C/EBPβ acts as an age-dependent transcription factor for
delta-secretase (AEP, also called legumain). This crucial protease cleaves both APP and Tau in human AD
brains and AD mouse models, promoting amyloidogenic pathway and neurofibrillary tangle (NFT) formation.
Inactivation of delta-secretase substantially decreases Aβ deposits and NFT aggregation and abolishes AD
pathologies in various AD mouse models. In our preliminary studies, we found that C/EBPβ binds ApoE
promoter and dictates ApoE mRNA transcription during aging. Knockout of C/EBPβ in 3xTg greatly reduces
ApoE levels and senile plaques. On the other hand, ApoE4 but not E3 strongly activates C/EBPβ in primary
neurons. Blockage of ApoE4 interaction with its receptor diminishes this effect. Moreover, 27-
hydroxycholesterol displays much stronger effect in stimulating C/EBPβ than cholesterol in the presence of
ApoE4. Hence, we hypothesize that ApoE4 and 27-oxycholesterol trigger C/EBPβ activation, which feeds
back and upregulates ApoE transcription in AD pathogenesis. Consequently, this vicious loop may
facilitate AD pathologies via escalating delta-secretase levels. To define the molecular mechanisms between
ApoE4/C/EBPβ crosstalk will provide an innovative insight into the pathological roles of ApoE4 in AD onset
and progression.
ApoE 4是阿尔茨海默病(Alzheimer's disease,AD)发病的主要遗传危险因子。在中枢神经
在中枢神经系统(CNS)中,ApoE主要由胶质细胞和星形胶质细胞产生,并通过ApoE将胆固醇转运到神经元
受体,其是低密度脂蛋白受体(LDLR)基因家族的成员。ApoE亚型-
与Aβ的特异性相互作用,即ApoE/Aβ复合物,调节Aβ水平,并参与Aβ
间隙C/EBPβ是一种炎性细胞因子调节的转录因子,可被Aβ激活,
好.有趣的是,我们最近报道C/EBPβ作为一个年龄依赖性转录因子,
δ-分泌酶(AEP,也称为豆科蛋白)。这种关键的蛋白酶在人类AD中切割APP和Tau
脑和AD小鼠模型,促进淀粉样蛋白生成途径和神经纤维缠结(NFT)形成。
δ-分泌酶的失活显著降低Aβ沉积和NFT聚集,并消除AD
在各种AD小鼠模型中的病理学。在我们的初步研究中,我们发现C/EBPβ与ApoE结合,
启动子,并决定衰老过程中ApoE mRNA的转录。在3xTg中敲除C/EBPβ大大降低了
ApoE水平和老年斑。另一方面,ApoE 4而不是E3在原发性肝癌中强烈激活C/EBPβ。
神经元阻断ApoE 4与其受体的相互作用会减弱这种作用。此外,27-
羟基胆固醇对C/EBPβ的刺激作用强于胆固醇,
载脂蛋白E4因此,我们假设ApoE 4和27-氧胆固醇触发C/EBPβ激活,
在AD发病机制中逆转和上调ApoE转录。因此,这种恶性循环
通过升高δ-分泌酶水平促进AD病理学。来确定
ApoE 4/C/EBPβ相互作用将为ApoE 4在AD发病中的病理作用提供新的见解
和进步。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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GUY Martin BENIAN其他文献
GUY Martin BENIAN的其他文献
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10340546 - 财政年份:2022
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ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease
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