APOE SIGNALING, NEUROBEHAVIOR,AND NEUROPLASTICITY

在过去的十年中，载脂蛋白E已经成为晚发性、散发性的最有效的危险因素之一 阿尔茨海默病(AD)。尽管大量研究极大地提高了对 载脂蛋白E及其受体，载脂蛋白E基因影响个体易感性的机制 广告仍不为人所知。我们知道特定的脂蛋白受体对于维持正常是必不可少的。 成年小鼠海马区的突触可塑性和学习记忆过程。配基- 载脂蛋白E与其受体之间的受体相互作用在 突触对正常的认知过程和观察到的扰动都有广泛的影响 公元早期。这一提议的总体假设表明，apoE作为一种异构体特异性信号 调节神经元突触可塑性和海马区依赖记忆形成的配体，是 易受FI淀粉样蛋白堆积变化的影响。 不同的载脂蛋白E亚型，配体卷轴和四个主要的载脂蛋白E受体结合这些配体 给这个系统增加了一个极其复杂的复杂程度。这项建议旨在更好地 了解apoE信号和apoE受体功能的四个重要方面： 1)影响载脂蛋白E受体加工的环境。 2)载脂蛋白E依赖性突触功能和记忆形成改变的机制。 3)特异性载脂蛋白E受体与载脂蛋白E亚型在受体信号转导中的相互作用 正在处理。 4)载脂蛋白E异构体信号转导和载脂蛋白E受体加工在病理过程中的作用 与阿尔茨海默氏症有关。 这些研究将首次确定载脂蛋白E亚型与特定受体的相互作用，以及这些亚型如何 相互作用可以影响中枢神经系统的功能。这些见解将在评估AD风险、制定新的 阿尔茨海默病的治疗策略，确定潜在的治疗药物靶点，以管理和 洞察涉及脂蛋白受体系统的其他与年龄相关的疾病。

In the past decade, apoE has emerged as one of the best validated risk factors for late-onset, sporadic Alzheimer's disease (AD). Despite a great deal of research that has significantly improved understanding of apoE and its receptors, the mechanism by which apoE genotype influences an individual's predisposition to AD remains unknown. We know that specific lipoprotein receptors are essential in maintaining normal synaptic plasticity and learning and memory processes in the adult mouse hippocampus. The ligand- receptor interaction between apoE and its receptors is well poised in the molecular framework of the synapse to have broad implications for both normal cognitive processes and the perturbations observed in early AD. The overall hypothesis of this proposal states that that apoE acts as an isoform-specific signaling ligand to modulate neuronal synaptic plasticity and hippocampal-dependent memory formation, and is susceptible to changes in fi amyloid accumulation. The different apoE isoforms, the ligand reelin and the four prominent apoE receptors that bind these ligands adds an exceedingly complicated level of complexity to this system. This proposal is designed to better understand four important aspects of apoE signaling and apoE receptor function: 1) The circumstances that influence apoE receptor processing. 2) The mechanisms that underlie apoE-dependent changes in synaptic function and memory formation. 3) The interactions between specific apoE receptors and apoE isoforms in receptor signaling and processing. 4) The role of apoE isoform signaling and apoE receptor processing in the pathological processes associated with Alzheimer's disease. These studies will be the first to identify interactions of apoE isoforms to specific receptors and how those interactions can affect CNS function. These insights will be valuable in assessing AD risk, formulating new treatment strategies for AD, identifying potential therapeutic drug targets for the management of AD and provide insight into other age-related disorders involving the lipoprotein receptor system.