Mechanistic studies of synaptopathies associated with Alzheimer's risk factors

项目总结/摘要 阿尔茨海默病（Alzheimer's Disease，AD）最早期的改变之一是突触传递功能障碍，因此， 干扰神经网络的信息处理。然而，尽管进行了深入研究， 导致突触功能障碍并因此导致认知能力下降的原因尚不清楚。因此，它具有根本性的 重要的是要了解参与AD的候选基因，如淀粉样前体蛋白（APP）和 超氧化物歧化酶（SOD）破坏突触信号传导。目前建议的科学前提是， 产生AD的动物模型，并采用基于遗传学的系统生物学方法， 基本了解AD如何改变神经元功能。与在以下方面的补充努力相比， 与其他系统不同的是，目前的建议是单神经元分辨率，专注于实时体内 突触受体和APP的细胞内转运，以及发现调节， 控制或修饰突触受体和神经传递的稳态和基因表达途径。 我们建立了转基因C. elegans获得新的见解， AD的病理生理学在初步的实验中，我们观察到突触功能的显着中断， 过表达SOD-1或APL-1的转基因蠕虫（C. SOD和APP的线虫同源物， 分别）。特别是，我们发现AMPA型离子型谷氨酸的运动介导转运 受体和谷氨酸门控电流被严重破坏，导致动物行为改变。 这些结果为研究突触后神经元的病理生理学提供了一个新的概念框架。 AD的功能障碍。 在这个提议中，我们测试了SOD-1和APL-1介导的突触功能破坏的机制模型， 我们概述了一种策略，以确定新的遗传修饰剂，恢复突触传递，在我们的转基因， AD模型。由于APP、SOD、突触蛋白、微管依赖性 马达和大多数细胞内信号通路，我们的研究将直接相关的 人类AD的病理生理学。此外，我们希望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相关的神经变性疾病的切入点。

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.