Synaptic damage in models of beta-amyloid associated pathology

他的新申请是要求对海马神经元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 似乎是老年人和阿尔茨海默氏症记忆缺陷的基础。从啮齿动物到人类， 海马体和相邻的互连结构主要与记忆有关。而 海马子区域内的解剖学连接性被合理地很好地描绘出来， 各子场对学习记忆功能的贡献尚不清楚。与此同时， 亚结构在损伤如脑缺血、老化后易受损伤和死亡 以及某些神经退行性疾病如阿尔茨海默病。特别是， 阿尔茨海默病相关的病理损伤在这个结构分离海马从其皮质 连通性。因此，这一大脑区域的选择性脆弱性可能是造成红衣主教的原因。 阿尔茨海默氏症的记忆障碍表现。指导这一研究的工作假设 程序是轴突和突触隔室的扰动，无论是通过结构或功能 损伤，导致早期突触功能障碍，并导致衰老中的学习和记忆缺陷， 神经变性这个项目将集中在海马体本身，特别是CA1和CAS 区域有两个主要目标。首先，我们将研究这些细胞的核心学习和记忆功能。 海马的两个亚区，使用这些神经元的新的、选择性的和短暂的失活 通过遗传和药理学的结合。这些操作将使用令人兴奋的新 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 在学习和记忆中的子区域是以前不可能的。第二，我们将调查机制 负责该区域的轴突和突触变化，特别是在阿尔茨海默病相关的 神经变性具体来说，我们将检查培养的神经元和各种小鼠模型， 淀粉样β蛋白引发的海马损伤的几种机制 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酶 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， 老年痴呆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海马体在记忆和神经退行性变中的作用。此外，A 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， 促进我们在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.