APO E Receptors and Modulation of Fast Axonal Transport

APO E 受体和快速轴突运输的调节

• 批准号: 6460608
• 负责人: Joachim J Herz
• 金额: $ 37.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460608
• 关键词: apolipoprotein E; axon; dynein ATPase; enzyme activity; gene targeting; genetically modified animals; intracellular transport; kinesin; laboratory mouse; mutant; neuronal transport; protein transport; receptor; synapses

DESCRIPTION (provided by applicant): Members of the low-density-lipoprotein (LDL) receptor gene family have recently been found to participate in signal transduction pathways during the development of the brain. Reelin, a large secreted protein that bears no resemblance to lipoproteins and is not involved in lipid transport, binds to the extracellular domains of two members of this gene family, termed VLDL receptor (VLDLR) and ApoE receptor 2 (ApoER2). Binding of this ligand activates a cytoplasmic signaling cascade that apparently involves tyrosine kinases as well as the serine/threonine kinases Cdk5 and GSK-3beta. Disruption of this pathway results in abnormal phosphorylation of the microtubule-associated protein tau and therefore is likely to impair axonal transport processes, which are dependent on the normal function of microtubules. ApoER2 and VLDLR both are expressed abundantly on the surface of embryonic neurons as well as on neurons in the mature brain, where they can also function as receptors for Apolipoprotein E (ApoE). ApoE exists in three major isoforms. One of these isoforms, ApoE4 is genetically associated with late-onset Alzheimer disease. The biochemical basis by which ApoE4 predisposes its carriers to late-onset Alzheimer disease is poorly understood. We hypothesize that ApoE4 acts as a competitor for signaling molecules such as Reelin and reduces their binding to the receptors on the neuronal surface, thereby impairing physiological signaling pathways that regulate neuronal transport and synaptic protein transport. This model would provide a mechanistic basis on which the loss of synapses, which correlates with dementia and precedes the formation of plaques and neurofibrillary tangles, could be explained. The goal of the current proposal is to elucidate the cytoplasmic signaling pathways that are activated by the binding of Reelin to its receptors on the neuronal cell surface and to study the effect of Reelin on axonal transport, the activity of molecular motors such as dynein and kinesin, and the transport of synaptic proteins to their target sites.

描述(由申请人提供)： 低密度脂蛋白(LDL)受体基因家族的成员最近 被发现参与了信号转导通路。 大脑的发育。Reelin，一种大的分泌蛋白质，不含 与脂蛋白相似，不参与脂类运输，结合 该基因家族中两个成员的胞外结构域，称为极低密度脂蛋白 VLDLR和ApoE受体2(ApoER2)。该配体的结合被激活 一种细胞质信号级联显然涉及酪氨酸激酶 以及丝氨酸/苏氨酸激酶CDK5和GSK-3β。扰乱这一点 通路导致微管相关蛋白异常磷酸化 蛋白tau，因此可能会损害轴突运输过程，这是 依赖于微管的正常功能。ApoER2和VLDLR都是 在胚胎神经元和神经元表面均有丰富的表达 在成熟的大脑中，它们也可以作为受体发挥作用 载脂蛋白E(ApoE)。载脂蛋白E以三种主要的亚型存在。这其中的一个 ApoE4的异构体与晚发性阿尔茨海默病的基因相关。 载脂蛋白E4使其携带者晚发的生化基础 人们对阿尔茨海默病知之甚少。我们假设载脂蛋白E4作为一个 Reelin等信号分子的竞争对手，并将它们的结合减少到 神经元表面的受体，从而损害生理 调节神经元转运和突触蛋白的信号通路 运输。这一模式将提供一种机制基础，在这种基础上 突触，它与痴呆症相关，并在斑块形成之前 和神经原纤维缠结，可以解释。当前的目标是 建议阐明被激活的细胞质信号通路 通过Reelin与其在神经细胞表面的受体结合，并 Reelin对轴突运输、分子活性的影响 运动，如动力蛋白和动蛋白，以及突触蛋白的运输 他们的目标地点。