Role of LDLR in regulating metabolism of Apolipoprotein E and Amyloid-beta

LDLR 在调节载脂蛋白 E 和淀粉样蛋白-β 代谢中的作用

基本信息

批准号：
9345995
负责人：
Jungsu Kim
金额：
$ 39.13万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9345995
关键词：
Abeta clearance Address Affect Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Apolipoprotein E Biology Brain CREB1 gene Cells Clinical Cognition Collaborations Computer Simulation Data Deposition Dimerization Genotype Hour In Vitro Knock-out Knockout Mice LDL-Receptor Related Protein 1 LDLR gene Length Lipids Lipoprotein Receptor Low Density Lipoprotein Receptor Mass Spectrum Analysis Mediating Memory Memory Loss Metabolism Methods Microdialysis Microglia Molecular Mus N-Methylaspartate Neurons Pathogenesis Pathologic Pathway interactions Pharmacology Phenotype Phosphorylation Physiologic pulse Protein Isoforms Proteins Receptor Gene Reporting Role Senile Plaques Signal Transduction Source Structure Structure-Activity Relationship Synapses Synaptic plasticity Testing Tissues Translating Translational Research amyloid formation amyloid precursor protein processing apolipoprotein E receptor 2 base cell type cytokine dimer experimental study genetic risk factor genetically modified cells in vivo innovation insight molecular dynamics mouse model neuroinflammation novel overexpression protein E protein aggregation reelin receptor simulation stable isotope synaptic function tau Proteins tau phosphorylation trafficking translational medicine treatment strategy ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for Alzheimer’s disease (AD). Prevailing evidence suggests that ApoE isoforms affect amyloid β (Aβ), tau, neuroinflammation, and synaptic plasticity. In addition to isoforms, alteration in ApoE protein levels has been shown to influence neuroinflammation and Aβ clearance. Previously, we reported the critical roles of ApoE receptor, low density lipoprotein receptor (LDLR), in regulating ApoE clearance and Aβ levels in the brain. Overexpression of LDLR in the brain dramatically inhibits amyloid formation by decreasing ApoE level and increasing Aβ clearance. These beneficial effects were seen with as little as just 2-fold over-expression of LDLR. However, translating these observations into therapy has been hampered by a poor understanding of cellular and molecular mechanism and a paucity of effective approach to regulate the levels of LDLR in the brain. To overcome this critical barrier, we propose to investigate cellular mechanism by which Inducible Degrader Of LDLR (IDOL) regulates LDLR, ApoE, Aβ, and tau. In collaboration with Dr. Tontonoz (HHMI, UCLA), we found that global deletion of IDOL gene dramatically increases LDLR levels and decreases apoE levels in the brain. IDOL is an E3 ubiquitin ligase that ubiquitinates LDLR and targets it for degradation. Importantly, loss of IDOL expression significantly reduced amyloid plaque burden and ameliorated neuroinflammation in an AD mouse model. Based on these strong preliminary data, we now propose to determine the cellular and molecular mechanism by which IDOL affects ApoE and Aβ using primary cells isolated from global and conditional knockout IDOL mouse model. We hypothesize that the beneficial effect of IDOL deletion is mediated through LDLR-mediated ApoE level reduction and ApoER2- mediated Reelin signaling. To test hour hypothesis, we will apply innovative methods, such as molecular dynamics simulation, in vivo stable isotope pulse chase mass spectrometry, and in vivo Aβ and cytokines microdialysis. Deciphering IDOL pathway in cellular details may help better understanding ApoE signaling in basic biology and AD.

项目摘要/摘要载脂蛋白E（APOE）基因型是阿尔茨海默氏病（AD）的强大遗传危险因素。盛行有证据表明，APOE同工型会影响淀粉样β（Aβ），TAU，神经炎症和突触可塑性。在除同工型外，APOE蛋白水平的改变已被证明会影响神经炎症和Aβ 清除。以前，我们报道了APOE受体，低密度脂蛋白受体（LDLR）的关键作用，在调节大脑中的APOE清除和Aβ水平时。大脑中LDLR的过表达急剧通过降低APOE水平并增加Aβ清除率，抑制淀粉样蛋白形成。这些有益的效果他们看到的只是LDLR的2倍过表达。但是，将这些观察结果转化为对细胞和分子机制的了解不足以及缺乏调节大脑中LDLR水平的有效方法。为了克服这一关键障碍，我们建议研究了细胞机制，通过这些机制，LDLR（偶像）的诱导降解器调节LDLR，APOE，Aβ和 tau。与Tontonoz博士（HHMI，UCLA）合作，我们发现偶像基因的全球删除极大地删除提高LDLR水平并降低大脑中的APOE水平。偶像是泛素化的E3泛素连接酶 LDLR并将其靶向降解。重要的是，偶像表达的丧失显着减少了淀粉样斑块 AD小鼠模型中的负担和改善神经炎症。基于这些强大的初步数据现在，我们建议确定偶像使用偶像影响ApoE和Aβ的细胞和分子机制从全球和条件基因敲除偶像小鼠模型中分离出来的主细胞。我们假设偶像缺失的有益作用是通过LDLR介导的APOE水平降低和apoer2-介导的介导的reelin信号传导。为了测试小时假设，我们将采用创新方法，例如分子动力学模拟，体内稳定的同位素脉冲追逐质谱法，体内Aβ和细胞因子微透析。细胞细节中的解密偶像途径可能有助于更好地理解APOE信号传导基本生物学和广告。