Impairment of axonal transport by Amyloid precursor protein and amyloid Beta-prot

他的新申请是请求为海马区的跨学科研究提供五年的支持 调节记忆的机制。了解这些机制至关重要，因为它们的损害 似乎是衰老和阿尔茨海默病中记忆缺陷的基础。从啮齿动物到人类， 海马体和相邻的相互连接的结构主要与记忆有关。而当 海马子区域内的解剖连接被合理地描绘出来，每一个 各亚区对学习和记忆功能的贡献尚不清楚。同时，大脑中的神经元 在老化过程中，亚结构容易在损伤后受损和死亡，如脑缺血。 以及某些神经退行性疾病，如阿尔茨海默病。特别是，一致的存在 在这个结构中阿尔茨海默病相关的病理损害将海马区与其皮质隔离开来 连通性。因此，这一大脑区域的选择性脆弱性很可能是红衣主教 阿尔茨海默病患者记忆障碍的表现。指导这一点的工作假说 程序是轴突和突触隔间的扰动，无论是通过结构上的还是功能上的 损伤，导致早期突触功能障碍，并导致学习和记忆障碍在衰老和 神经退行性变。本课程将重点介绍海马体，特别是CA1和CAS 各地区心中有两个主要目标。首先，我们将研究这些神经元的核心学习和记忆功能 用一种新的、选择性的和瞬时的失活方法使这些神经元失活 通过遗传和药理学手段的结合。这些操作将使用激动人心的新技术 索尔克研究所开发的技术，将使我们能够可逆地探测CA1和CA3的功能 在学习和记忆方面的分区以前是不可能的。第二，我们将研究其机制。 负责该区域的轴突和突触的变化，特别是与阿尔茨海默病相关的 神经退行性变。具体地说，我们将检查培养的神经元和各种小鼠模型来测试 淀粉样β蛋白引发海马区损伤的几种机制 和淀粉样前体蛋白。我们认为淀粉样前体蛋白和各种蛋白水解物 包括淀粉样β蛋白在内的产物以不同的方式导致突触和轴突损伤。 阿尔茨海默氏症。通过汇集具有独特专业知识和背景的实验室，我们建议 通过多学科方法探索记忆中的海马体和神经退行性变中的海马体。此外，一个 该计划的独特和关键方面是共享常见的小鼠品系、试剂和载体，以 促进我们四个项目中提出的合作研究。

his new application is to request five years of support for an interdisciplinary investigation of hippocampal mechanisms mediating memory. Understanding these mechanisms is vital because their impairment appears to underlie the memory deficits seen in aging and in Alzheimer's disease. From rodents to humans, the hippocampus and adjacent interconnected structures are principally concerned with memory. While the anatomical connectivity within the subfields of the hippocampus is reasonably well delineated, how each of the subfields contribute to learning and memory functions are not clear. At the same time, neurons within the substructures are susceptible to damage and death following injury such as cerebral ischemia, in aging and in certain neurodegenerative diseases such as Alzheimer's disease. In particular, consistent presence of Alzheimer associated pathological lesions in this structure isolates the hippocampus from its cortical connectivity. Consequently, the selective vulnerability of this brain region is likely responsible for the cardinal manifestations of memory impairment in Alzheimer's disease. The working hypothesis that guides this program is that perturbations of axonal and synaptic compartments, either through structural or functional damage, lead to early synaptic dysfunction and result in learning and memory deficits in aging and neurodegeneration. This program will focus on the hippocampus proper, particularly the CA1 and CAS regions with two major goals in mind. First, we will examine the core learning and memory functions of these two subregions of the hippocampus using a novel, selective, and transient inactivation of these neurons through a combination of genetic and pharmacologic means. These manipulations will use exciting new technology developed at The Salk Institute and will allow us to reversibly probe the function of CA1 and CA3 subregions in learning and memory not previously possible. Second, we will investigate the mechanisms responsible for axonal and synaptic changes in this region, particularly in Alzheimer's disease related neurodegeneration. Specifically, we will examine cultured neurons and various mouse models to test several mechanisms that may contribute to hippocampal injury that are initiated by the amyloid beta-protein and the amyloid precursor protein. We propose that both amyloid precursor protein and various proteolytic products, including amyloid beta-protein, contribute in different ways to synaptic and axonal damage in Alzheimer's disease. By bringing together laboratories with unique expertise and background, we propose to probe the hippocampus in memory and in neurodegeneration by a multi-disciplinary approach. Further, a unique and key aspect of this Program is the sharing of common mouse strains, reagents, and vectors to facilitate the collaborative studies proposed in our four Projects.