Mechanisms of Reelin Signaling in the Adult Hippocampus

描述(申请人提供)：载脂蛋白E(ApoE)与阿尔茨海默病之间存在功能联系。载脂蛋白E使其携带者患上这种疾病的潜在生化机制尚不清楚，目前仍在争论中。一种模型表明，在神经元表面大量表达的载脂蛋白E受体家族的成员，特别是APOE2和VLDL受体，可能参与了这一病理过程。其中两个ApoE受体，VLDL受体和ApoER2，也是Reelin的受体，Reelin是一种信号蛋白，在大脑发育过程中调节神经元的迁移。成年的GABA能中间神经元表达Reelin，与海马区APOE2和VLDL受体的高表达相结合，强烈表明这些系统在成人中枢神经系统中的作用。这一建议的基础是一种假设，即在成人中枢神经系统中，Reelin/APOE2/VLDL受体系统具有作为神经传递调节器的功能。为了更好地了解该受体系统在哺乳动物海马体功能中的作用，我们将进行四个具体目标： 目的1：确定APOE2和VLDL受体缺陷的小鼠是否表现出学习记忆和海马概要功能的缺陷。 目的：研究应用Reelin和阻断Reelin信号对成年大鼠海马区突触传递和可塑性的影响。 目的3：验证Reelin通过Src酪氨酸激酶以ApoER2/VLDL受体依赖的方式磷酸化NMDA受体的假说。 目的4：确定ApoER2胞质结构域的结构/功能关系。 这些研究将对脂蛋白受体APOE2和VLDL在哺乳动物学习和记忆机制以及海马区突触传递和可塑性中的作用提供一个基本的了解。此外，这些研究将首次深入了解通过这些受体调节海马区功能的Reelin信号机制。总体而言，这项工作将有助于阐明这些载脂蛋白E受体在阿尔茨海默病等神经退行性疾病中的潜在作用。

DESCRIPTION (provided by applicant): There is a functional connection between Apolipoprotein E (ApoE) and Alzheimer's disease. The underlying biochemical mechanism by which ApoE predisposes its carriers to this disease is not known and is under debate. One model suggests that members of a family of ApoE receptors that are abundantly expressed on the surface of neurons, specifically the ApoE2 and VLDL receptors, may be involved in this pathological process. Two of these ApoE receptors, the VLDL receptor and the ApoER2, are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. Adult expression of Reelin by GABA-ergic interneurons coupled to a high expression of ApoE2 and VLDL receptors in the hippocampus strongly suggests a role for these systems in adult CNS. The basis for this proposal is the hypothesis that there is a function of the Reelin/ApoE2/VLDL receptor system as a modulator of neurotransmission in the adult CNS. To better understand the role of this receptor system in mammalian hippocampal function, we will undertake four specific aims: Aim 1: Determine if mice deficient for ApoE2 and VLDL receptors exhibit deficits in learning and memory and hippocampal synoptic function. Aim 2: Determine the effect of Reelin application and Reelin signaling disruption on adult hippocampal synaptic transmission and plasticity. Aim 3: Test the hypothesis that Reelin acts through Src tyrosine kinase to phosphorylate NMDA receptors in an ApoER2/VLDL receptor-dependent manner. Aim 4: Determine the structure/function relationship for ApoER2 cytoplasmic domains. These studies will provide a basic understanding of the role for the lipoprotein receptors ApoE2 and VLDL in mammalian learning and memory mechanisms and hippocampal synaptic transmission and plasticity. Moreover, these studies will provide the first insight into the mechanisms of Reelin signaling through these receptors to modulate hippocampal function. Overall, this work will help shed light on the potential role of these ApoE receptors in neurodegenerative disorders, such as Alzheimer's disease.