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：
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
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：
https://reporter.nih.gov/project-details/10319519
关键词：
27-hydroxycholesterol 3xTg-AD mouse Abeta clearance Age of Onset Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos 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

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.

ApoE4 是中枢神经系统中阿尔茨海默病 (AD) 发病机制的主要遗传风险因素。 ApoE主要由神经胶质细胞和星形胶质细胞产生，通过ApoE将胆固醇转运至神经元受体，属于低密度脂蛋白受体 (LDLR) 基因家族的成员。与 Aβ 的特异性相互作用，即 ApoE/Aβ 复合物，调节 Aβ 水平并与 Aβ 相关 C/EBPβ 是一种炎症细胞因子调节的转录因子，可被 Aβ 激活。神秘的是，我们最近报道了 C/EBPβ 作为年龄依赖性转录因子。 δ-分泌酶（AEP，也称为 legumain）在人类 AD 中可裂解 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原纤维缠结 (NFT) 的形成。 δ-分泌酶失活可显着减少 Aβ 沉积和 NFT 聚集并消除 AD 在我们的初步研究中，我们发现 C/EBPβ 结合 ApoE。启动子并决定衰老过程中 ApoE mRNA 的转录，从而极大地敲除 3xTg 中的 C/EBPβ。 ApoE 水平和老年斑另一方面，ApoE4 而不是 E3 强烈激活原发性的 C/EBPβ。此外，阻断 ApoE4 与其受体的相互作用会减弱这种效应。在存在羟基胆固醇的情况下，羟基胆固醇在刺激 C/EBPβ 方面表现出比胆固醇更强的作用。因此，我们研究 ApoE4 和 27-羟胆固醇触发 C/EBPβ 激活，从而促进 C/EBPβ 激活。研究表明，AD 发病机制中 ApoE 转录上调，这种恶性循环可能存在。通过升高 δ 分泌酶水平促进 AD 病理学定义之间的分子机制。 ApoE4/C/EBPβ 串扰将为 ApoE4 在 AD 发病中的病理作用提供创新的见解和进展。