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

• 批准号: 10533321
• 负责人: GUY Martin BENIAN
• 金额: $ 46.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10533321
• 关键词: 27-hydroxycholesterol; 3xTg-AD mouse; Abeta clearance; Age of Onset; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Applications Grants; Astrocytes; Back; Binding; Binding Proteins; Biochemical; Biological Assay; Brain; CCAAT-Enhancer-Binding Proteins; Cardiovascular Diseases; Cells; Central Nervous System; Cholesterol; Cholesterol Homeostasis; Complex; Consensus; Deposition; Disease Progression; Event; Family; Fatty acid glycerol esters; Feeds; Future; Gene Family; Genetic Transcription; Goals; Human; Inflammatory; Interleukin-6; Knock-out; Knowledge; LDL-Receptor Related Protein 1; Liver; Low Density Lipoprotein Receptor; Macrophage; Mediating; Messenger RNA; Molecular; Mus; Neurofibrillary Tangles; Neuroglia; Neurons; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Peripheral; Persons; Play; Production; Protein Isoforms; Proteins; Reporting; Risk; Role; Senile Plaques; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; Up-Regulation; Viral Vector; YY1 Transcription Factor; adipocyte differentiation; age related; apolipoprotein E-3; apolipoprotein E-4; asparaginylendopeptidase; cytokine; factor C; genetic risk factor; innovation; insight; lipid metabolism; member; mouse model; neurofibrillary tangle formation; overexpression; promoter; receptor; secretase; spatiotemporal; tau Proteins; tau expression; tau mutation; transcription factor

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.

APOE4是阿尔茨海默氏病（AD）发病机理的主要遗传危险因素。中央紧张 系统（CNS），APOE主要由胶质细胞和星形胶质细胞产生，并通过APOE将胆固醇传输到神经元 受体，是低密度脂蛋白受体（LDLR）基因家族的成员。 ApoE同工型 与Aβ的特定相互作用，即APOE/Aβ复合物，调节Aβ水平，并在Aβ中实现 清除。 C/EBPβ是一种炎性细胞因子调节的转录因子，可以被Aβ激活为 出色地。有趣的是，我们最近报道了C/EBPβ充当年龄依赖性转录因子 三角洲分泌酶（AEP，也称为Legumain）。这种关键的蛋白酶在人类广告中都裂解了应用程序和tau 大脑和AD小鼠模型，促进淀粉样蛋白生成途径和神经纤维缠结（NFT）的形成。 三角洲分泌酶的失活实质上下降了Aβ沉积和NFT聚集并废除AD 各种AD鼠标模型中的病理。在我们的初步研究中，我们发现C/EBPβ结合了APOE 启动子并指示衰老期间APOE mRNA转录。 3XTG中的C/EBPβ大大减少了 Apoe水平和老年斑块。另一方面，APOE4而不是E3强烈激活初级的C/EBPβ 神经元。 APOE4与其受体相互作用的阻塞会减少这种效果。而且，27- 在存在下，羟基胆固醇在刺激C/EBPβ方面表现出比胆固醇的效果要强得多。 APOE4。因此，我们假设APOE4和27-氧胆固醇触发C/EBPβ激活 背部并上调AD发病机理中的APOE转录。因此，这个恶毒的循环可能 通过升级三角洲分泌酶水平来促进AD病理。定义分子机制 APOE4/C/EBPβ串扰将为APOE4在AD发作中的病理作用提供创新的见解 和进展。