ApoE and ApoER2 mediated regulation of APP metabolism

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因。AD的特征性标志的特征在于存在由A2肽组成的淀粉样蛋白斑块和由过度磷酸化的tau组成的缠结。ApoE（载脂蛋白E），一种脑内胆固醇载体，是晚发性AD（65岁以前发病）唯一已知和最广泛接受的遗传风险因素。APOE基因的遗传变异与AD的迟发性相关。在人类中，APOE有三个多态性等位基因：E2，E3和E4，它们彼此相差一个氨基酸。APOE 4与AD早发（65岁之前发病）的几率增加相关，占AD遗传风险的40-50%。 ApoE与细胞表面受体如ApoER 2结合，将胆固醇和其他必需脂质转运到神经元。ApoER 2主要在脑中表达，并参与神经元迁移、皮质层压和突触功能。有趣的是，apoE受体通过β-分泌酶（如APP）进行蛋白水解裂解，释放出与常见衔接蛋白相互作用的细胞内结构域。ApoER 2结合细胞外配体如Reelin和细胞内配体如Fe 65、X11、Dab 1，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。近年来，大量证据表明ApoE受体直接或间接地改变APP的表达、分布和运输，从而改变APP的加工和A2的产生。APP和ApoER 2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。 本提案的目的是确定ApoER 2是否与APP竞争或结合衔接蛋白，以及apoE同种型是否差异调节这种相互作用以改变APP加工和A2产生，以及apoE同种型是否在体外和体内改变ApoER 2与APP之间的相互作用以改变A2产生。这项研究将有助于确定apoE在中枢神经系统中的功能，并确定一种新的机制，ApoE改变A2的生产在体内。如果ApoER 2以ApoE亚型依赖性机制改变APP代谢，则ApoER 2可以是假定的药物靶点。 公共卫生相关性：神经退行性疾病，如阿尔茨海默病，在心理和经济上给社会造成巨大负担。该项目的目标是确定apoE（唯一已知的风险因素）调节APP代谢和A2生成的机制。该提案中的研究旨在更深入地了解疾病进展的机制，希望这种理解有一天可能导致预防或减缓疾病的进展。

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.