ApoE and ApoER2 mediated regulation of APP metabolism

ApoE 和 ApoER2 介导的 APP 代谢调节

基本信息

批准号：
8128074
负责人：
Preeti Khandelwal
金额：
$ 1.52万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8128074
关键词：
Accounting Adaptor Signaling Protein Affect Age Alleles Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Precursor Apolipoprotein E Binding Brain Cell Surface Receptors Cerebrum Characteristics Cholesterol Dementia Dendritic Spines Development Disease Drug Delivery Systems Elderly Gene Transfer Generations Genes Genetic Risk Genetic Variation Goals Human In Vitro Knock-in Mouse LDL-Receptor Related Protein 1 Late Onset Alzheimer Disease Lead Ligand Binding Ligands Lipids Mediating Metabolic Pathway Metabolism Modeling Modification Mus Nerve Degeneration Neurofibrillary Tangles Neurons Onset of illness Peptides Presenile Alzheimer Dementia Prevention Production Protein Isoforms Reagent Regulation Research Risk Risk Factors Senile Plaques Signal Transduction Societies Synaptic plasticity Techniques Testing amyloid peptide amyloid precursor protein processing apolipoprotein E receptor 2 computerized data processing extracellular genetic risk factor in vivo migration nervous system disorder novel receptor secretase synaptic function tau Proteins trafficking

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The characteristic hallmark of AD is characterized by the presence of amyloid plaques, composed A2 peptide, and tangles composed of hyperphosporylated tau. ApoE (Apolipoprotein E), a cholesterol carrier in the brain is the only known and most widely accepted genetic risk factor for late onset AD (Onset before age d65). Genetic variation in the APOE gene has been associated with late-onset of AD. In humans, APOE has three polymorphic alleles: E2, E3, and E4 which differ from each other by one amino acid. APOE4 is associated with increased odds of early onset of AD (onset before age 65) and accounts for up to 40-50% of genetic risk of AD. ApoE binds to cell surface receptors like ApoER2, to transport cholesterol and other essential lipids to the neurons. ApoER2 is predominantly expressed in the brain and is involved in neuronal migration, cortical lamination, and synapse function. Interestingly, apoE receptors undergo proteolytic cleavage by -secretase like APP, releasing intracellular domains that interact with common adaptor proteins. ApoER2 binds extracellular ligands like Reelin, and intracellular ligands like Fe65, X11, Dab1, affecting in its trafficking and /or signaling. These modifications are crucial for neuronal migration, dendritic spine development, and synaptic plasticity. Over the past few years, a large amount of evidence shows that ApoE receptors directly or indirectly alter expression, distribution and trafficking of APP, thereby altering APP processing and A2 production. APP and ApoER2 interact via intra and extracellular ligands, binding of which can alter APP processing and A2 production. The goal of this proposal is to determine if ApoER2 competes or associates with APP for adaptor proteins and if apoE isoforms differentially regulate this interaction to alter APP processing and A2 production and if apoE isoforms alter the interaction between ApoER2 and APP in vitro and in vivo to alter A2 production. This study will help define the function of apoE in the CNS, and identify a novel mechanism by which ApoE alters A2 production in vivo. If ApoER2 alters APP metabolism in an ApoE isoform dependent mechanism, ApoER2 can be a putative drug target PUBLIC HEALTH RELEVANCE: Neurodegenerative like Alzheimer's disease cause an immense burden on society both psychologically and financially. The goal of this project is to identify the mechanism by which apoE, the only know risk factor regulates APP metabolism and A2 generation. The research in this proposal seeks a deeper understanding of the mechanisms that underlie the advancement of the diseases with the hope that this understanding may one day lead to their prevention or slowed progression.

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆的最常见原因。 AD 的特征是存在由 A2 肽组成的淀粉样斑块和由过度磷酸化 tau 蛋白组成的缠结。 ApoE（载脂蛋白 E）是大脑中的胆固醇载体，是唯一已知且最广泛接受的迟发性 AD（d65 岁之前发病）的遗传风险因素。 APOE 基因的遗传变异与迟发性 AD 相关。在人类中，APOE 具有三个多态性等位基因：E2、E3 和 E4，彼此相差一个氨基酸。 APOE4 与 AD 早期发病（65 岁之前发病）的几率增加有关，占 AD 遗传风险的 40-50%。 ApoE 与 ApoER2 等细胞表面受体结合，将胆固醇和其他必需脂质转运至神经元。 ApoER2 主要在大脑中表达，参与神经元迁移、皮质分层和突触功能。有趣的是，apoE 受体会被 APP 等分泌酶进行蛋白水解切割，释放出与常见接头蛋白相互作用的胞内结构域。 ApoER2 结合细胞外配体（如 Reelin）和细胞内配体（如 Fe65、X11、Dab1），影响其运输和/或信号传导。这些修饰对于神经元迁移、树突棘发育和突触可塑性至关重要。过去几年，大量证据表明ApoE受体直接或间接改变APP的表达、分布和运输，从而改变APP的加工和A2的产生。 APP 和 ApoER2 通过细胞内和细胞外配体相互作用，其结合可以改变 APP 加工和 A2 产生。该提案的目标是确定 ApoER2 是否与 APP 竞争或结合接头蛋白，以及 apoE 亚型是否差异性地调节这种相互作用以改变 APP 加工和 A2 的产生，以及 apoE 亚型是否在体外和体内改变 ApoER2 和 APP 之间的相互作用改变 A2 的生产。这项研究将有助于定义 apoE 在 CNS 中的功能，并确定 ApoE 改变体内 A2 产生的新机制。如果 ApoER2 以 ApoE 异构体依赖性机制改变 APP 代谢，则 ApoER2 可以成为假定的药物靶点公共卫生相关性：像阿尔茨海默病这样的神经退行性疾病给社会带来了巨大的心理和经济负担。该项目的目标是确定 apoE（唯一已知的危险因素）调节 APP 代谢和 A2 生成的机制。该提案中的研究寻求更深入地了解疾病进展的机制，希望这种理解有一天能够预防或减缓疾病的进展。