APOE SIGNALING, NEUROBEHAVIOR,AND NEUROPLASTICITY

在过去的十年中，apoE已成为晚发性、散发性、 阿尔茨海默病（AD）。尽管大量的研究已经大大提高了对 apoE及其受体，apoE基因型影响个体易感性的机制 AD仍然未知。我们知道特定的脂蛋白受体在维持正常的 突触可塑性与成年小鼠海马的学习记忆过程。配体- apoE及其受体之间的受体相互作用在apoE的分子框架中很好地平衡， 突触对正常的认知过程和观察到的扰动都有广泛的影响， 早期AD这个提议的总体假设是apoE作为一种亚型特异性信号传导， 配体调节神经元突触可塑性和突触依赖性记忆形成， 易受β淀粉样蛋白积累变化的影响。 不同的apoE亚型，配体reelin和结合这些配体的四种主要apoE受体 给这个系统增加了极其复杂的复杂性。该提案旨在更好地 了解apoE信号传导和apoE受体功能的四个重要方面： 1)影响apoE受体处理的环境。 2)突触功能和记忆形成中apoE依赖性变化的机制。 3)特异性apoE受体和apoE亚型在受体信号传导中的相互作用， 处理. 4)载脂蛋白E亚型信号转导及受体加工在病理过程中的作用 与老年痴呆症有关 这些研究将是第一个确定apoE亚型与特定受体的相互作用，以及这些受体如何与apoE亚型相互作用的研究。 相互作用可影响CNS功能。这些见解将在评估AD风险，制定新的 AD的治疗策略，确定用于管理AD的潜在治疗药物靶点， 提供了对其他涉及脂蛋白受体系统的年龄相关疾病的深入了解。

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.