Mechanistic studies of synaptopathies associated with Alzheimer's risk factors

项目摘要/摘要 阿尔茨海默病(AD)最早的变化之一是突触传递功能障碍，因此 通过神经网络干扰信息处理。然而，尽管进行了密集的研究，但这些因素 导致突触功能障碍，从而导致认知能力下降的原因还不清楚。因此，它具有根本性。 了解AD候选基因，如淀粉样前体蛋白(APP)和 超氧化物歧化酶(SOD)干扰突触信号。目前提案的科学前提是 建立AD的动物模型，并采用基于遗传学的系统生物学方法来获得 阿尔茨海默病如何改变神经元功能的基本理解(S)。与以下方面的互补努力形成对比 其他系统，当前提议的不同之处是单个神经元的分辨率，重点是活体内的实时 突触受体和APP的细胞内运输，以及发现调节的系统性努力， 控制或改变突触受体和神经传递的动态平衡和基因表达途径。 我们已经对转基因线虫中超氧化物歧化酶和APP的过度表达进行了建模，以获得对 阿尔茨海默病的病理生理学。在初步实验中，我们观察到突触功能显著中断。 过表达SOD-1或APL-1(线虫的SOD和APP的同源物， )。特别是，我们发现AMPA型离子型谷氨酸的运动介导的转运 受体和谷氨酸门控电流严重中断，导致动物行为改变。 这些结果为研究突触的病理生理学提供了一个新的概念框架 阿尔茨海默病的功能障碍。 在这项建议中，我们测试了SOD-1和APL-1介导的突触功能破坏的机制模型，并 我们概述了一种策略，以确定在我们的转基因中恢复突触传递的新的遗传修饰物 AD的模型。由于APP、SOD、突触蛋白、微管依赖的进化保守 马达和大多数细胞内信号通路，我们的研究将直接与 人类阿尔茨海默病的病理生理学。此外，我们预计我们的研究将提供新的治疗策略， 以及治疗AD和其他与APP和SOD相关的神经退行性疾病的切入点。

PROJECT SUMMARY/ABSTRACT One of the earliest changes in Alzheimer’s Disease (AD) is dysfunction of synaptic transmission, thus interfering with information processing by neuronal networks. However, despite intensive study, the factors contributing to synaptic dysfunction, and thus cognitive decline, are not understood. Thus, it is of fundamental importance to understand how candidate genes implicated in AD such as amyloid precursor protein (APP) and superoxide dismutase (SOD) disrupt synaptic signaling. The scientific premise of the current proposal is to generate animal models of AD and undertake a genetics-based, systems biology approach to gain a fundamental understanding of how AD changes neuronal function(s). In contrast to complementary efforts in other systems, what distinguishes the current proposal is single neuron resolution, a focus on real-time in vivo intracellular transport of synaptic receptors and APP, and a systematic effort to discover regulatory, homeostatic and gene expression pathways that control or modify synaptic receptors and neurotransmission. We have modeled the overexpression of SOD and APP in transgenic C. elegans to gain new insights into the pathophysiology of AD. In preliminary experiments, we observed striking disruption of synaptic function in transgenic worms that overexpressed either SOD-1 or APL-1 (C. elegans homologs of SOD and APP, respectively). In particular, we found that motor-mediated transport of AMPA-type ionotropic glutamate receptors and glutamate-gated currents were severely disrupted, leading to altered behavior of the animals. These results provide a new conceptual framework for investigating the pathophysiology of synaptic dysfunction in AD. In this proposal, we test mechanistic models of SOD-1 and APL-1 mediated disruption of synaptic function, and we outline a strategy to identify novel genetic modifiers that restore synaptic transmission in our transgenic models of AD. Because of evolutionary conservation of APP, SOD, synaptic proteins, microtubule-dependent motors and most intracellular signaling pathways, our studies will have immediate relevance to the pathophysiology of AD in humans. Additionally, we expect our studies will provide new therapeutic strategies, and entry points for the treatment of AD and other neurodegenerative disorders associated with APP and SOD.