ApoE and ApoER2 mediated regulation of APP metabolism

描述(申请人提供)：阿尔茨海默病(AD)是导致老年人痴呆症的最常见原因。阿尔茨海默病的特征特征是存在淀粉样斑块，由A2多肽组成，以及由过度磷酸化的tau组成的缠结。载脂蛋白E(载脂蛋白E)是大脑中的一种胆固醇携带者，是唯一已知和最被广泛接受的晚发性AD(在D65岁之前发病)的遗传风险因素。载脂蛋白E基因的遗传变异与迟发性阿尔茨海默病有关。在人类中，APOE有三个多态等位基因：E2、E3和E4，它们之间存在一个氨基酸差异。载脂蛋白E4与AD早期发病(65岁之前发病)的几率增加有关，并占AD遗传风险的40%-50%。APOE与ApoER2等细胞表面受体结合，将胆固醇和其他必要的脂质输送到神经元。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受体通过类似APP的分泌酶进行蛋白水解性切割，释放与普通接头蛋白相互作用的胞内结构域。ApoER2结合细胞外配体如Reelin，以及细胞内配体如Fe65、X11、Dab1，影响其运输和/或信号转导。这些修饰对神经元迁移、树突棘发育和突触可塑性至关重要。近年来，大量证据表明，载脂蛋白E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通过细胞内外配体相互作用，这些配体的结合可以改变APP的加工和A2的产生。这项建议的目的是确定ApoER2是否与APP竞争或结合接头蛋白，apoE亚型是否通过差异调节这种相互作用来改变APP的加工和A2的产生，以及apoE亚型是否在体外和体内改变ApoER2和APP之间的相互作用以改变A2的产生。本研究将有助于确定载脂蛋白E在中枢神经系统中的功能，并确定载脂蛋白E在体内改变A2产生的新机制。如果ApoER2以ApoE异构体依赖机制改变APP代谢，ApoER2可能是一个潜在的药物靶点 公共卫生相关性：像阿尔茨海默氏症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(唯一已知的风险因子)调节APP新陈代谢和A2生成的机制。这项建议中的研究试图更深入地了解疾病发展的基础机制，希望有一天这种了解可能会导致疾病的预防或减缓进展。

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.