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: 10319519
• 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/10319519
• 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; Cholesterol; Cholesterol Homeostasis; Complex; Consensus; Deposition; Disease Progression; E protein; Event; Family; Fatty acid glycerol esters; Feeds; Future; Gene Family; Genetic Transcription; Goals; Human; Inflammatory; Interleukin-6; Knock-out; Knowledge; Kupffer Cells; LDL-Receptor Related Protein 1; Low Density Lipoprotein Receptor; Mediating; Messenger RNA; Molecular; Mus; Neuraxis; Neurofibrillary Tangles; Neuroglia; Neurons; Onset of illness; Oxides; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Peripheral; Persons; Play; Production; Protein Isoforms; Proteins; Reporting; Risk; Role; Senile Plaques; Testing; Therapeutic Intervention; Time; Tissues; Transgenic Mice; Up-Regulation; Viral Vector; YY1 Transcription Factor; adipocyte differentiation; age related; apolipoprotein E-4; asparaginylendopeptidase; cytokine; factor C; genetic risk factor; innovation; insight; lipid metabolism; macrophage; 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.

载脂蛋白E4是阿尔茨海默病(AD)发病的主要遗传危险因素。在中枢神经 ApoE主要由胶质细胞和星形胶质细胞产生，并通过ApoE将胆固醇输送到神经元 受体，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，即载脂蛋白E/Aβ复合体，调节Aβ水平，并与Aβ有关 通行证。C/eBPβ是炎性细胞因子调节的转录因子，可被βAS激活 井。有趣的是，我们最近报道了C/eBPβ作为一种年龄依赖的转录因子 三角洲分泌酶(AEP，又称豆类)。这种关键的蛋白水解酶在人类AD中同时裂解APP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。 β-分泌酶的失活显著减少了Aβ沉积和NFT聚集，并消除了AD 各种AD小鼠模型的病理改变。在我们的初步研究中，我们发现C/EBPβ与载脂蛋白E结合 在衰老过程中启动并决定ApoE mRNA的转录。C/EBPβ在3xTg中的敲除大大减少 载脂蛋白E水平和老年斑块。另一方面，载脂蛋白E4而不是E3强烈激活初级C/EBPβ 神经元。阻断载脂蛋白E4与其受体的相互作用可减弱这种作用。此外，27- 羟基胆固醇对C/eBPβ的刺激作用比胆固醇强得多 载脂蛋白E4.因此，我们假设载脂蛋白E4和27-氧胆固醇触发C/EBPβ激活，从而为 逆转和上调载脂蛋白E转录在AD发病机制中的作用因此，这种恶性循环可能 通过升高增量分泌酶水平促进AD病理。为了定义分子机制， 载脂蛋白E4/C/EBPβ串扰将为研究载脂蛋白E4在AD发病中的病理作用提供新的视角 和进步。