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.

ApoE4是阿尔茨海默病（AD）发病的主要遗传危险因子。在中枢神经