ApoE and ApoER2 mediated regulation of APP metabolism

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆症的最常见原因。AD的特征性标志是存在由A2肽组成的淀粉样斑块和由高磷酸化的tau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（65岁前发病）的遗传风险因素。APOE基因的遗传变异与AD的晚发性有关。在人类中，APOE有三个多态等位基因：E2， E3和E4，它们彼此之间只相差一个氨基酸。APOE4与早发性阿尔茨海默病（65岁前发病）的几率增加有关，占阿尔茨海默病遗传风险的40-50%。ApoE与细胞表面受体如ApoER2结合，将胆固醇和其他必需脂质运输到神经元。ApoER2主要在大脑中表达，并参与神经元迁移、皮层层压和突触功能。有趣的是，apoE受体通过-分泌酶如APP进行蛋白水解裂解，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。在过去的几年里，大量证据表明ApoE受体直接或间接地改变了APP的表达、分布和贩运，从而改变了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，结合可以改变APP的加工和A2的产生。本研究的目的是确定ApoER2是否与APP竞争或结合以获取衔接蛋白，apoE异构体是否通过调节这种相互作用来改变APP的加工和A2的产生，以及apoE异构体是否通过改变ApoER2和APP在体内和体外的相互作用来改变A2的产生。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apoE在体内改变A2生成的新机制。如果ApoER2以ApoE亚型依赖的机制改变APP代谢，那么ApoER2可能是一个假定的药物靶点

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.