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.

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，也称为豆荚蛋白）。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。