Mechanisms of Reelin Signaling in the Adult Hippocampus

描述（由申请人提供）：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使其携带者易患这种疾病的潜在生化机制尚不清楚，而且还在争论中。一种模型表明，在神经元表面大量表达的ApoE受体家族成员，特别是ApoE2和VLDL受体，可能参与了这一病理过程。其中两种ApoE受体，VLDL受体和ApoER2受体，也是Reelin的受体，Reelin是一种调节大脑发育过程中神经元迁移的信号蛋白。在成人中枢神经系统中，gaba能介导的Reelin的表达与ApoE2和VLDL受体在海马中的高表达强烈提示了这些系统的作用。这一建议的基础是假设Reelin/ApoE2/VLDL受体系统在成人中枢神经系统中作为神经传递的调节剂。为了更好地理解这种受体系统在哺乳动物海马功能中的作用，我们将承担四个具体目标：

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.