Mechanisms of Developmental Plasticity in the Mammalian Olfactory System

项目摘要 阿尔茨海默病(AD)对个人的健康造成毁灭性的后果， 社区和社会。阿尔茨海默病的根本原因尚不清楚。淀粉样蛋白 β42被认为与AD病理有关，其形成的淀粉样斑块被认为是导致 阿尔茨海默病患者的神经元死亡。深入的研究已经确定了α-，β和γ- 分泌酶作为加工酶处理淀粉样前体蛋白(APP)以产生 APP、Aβ蛋白的可溶性形式和胞内信号域。然而，如何应用 加工是由其他蛋白质控制和调节的，以及不同形式的APP 蛋白分解产物的功能，目前仍不清楚。 在这个补充应用程序中，我们建议确定APP的交互伙伴，一个 APP的突变和致病形式及其切割产物，以阐明涉及的途径 在APP的贩运和加工中，以及各种蛋白水解物在 正常和病理状态。我们将利用APEX2融合蛋白，一种新的方法来 可以非常准确地标记紧密相关的蛋白质来实现这一目标。我们会 在小鼠嗅觉系统中进行这组实验。阿尔茨海默氏症患者，嗅觉 功能障碍是最早的病理表现之一。APP基因突变形式的表达 导致轴突投射模式和突触连接的戏剧性变化。体能 嗅觉感觉神经元及其轴突在不同的隔室中的分离使其成为 易于访问的系统，将轴突中的蛋白质功能与细胞体中的蛋白质功能分离。 这项研究将提供急需的活体检查的过程和相互作用的路径 带APP。 这项研究与家长助学金有关。家长奖助金的主要目标是了解 精确神经元发育可塑性的细胞和分子机制 大脑中的连接。在出生后早期的大脑发育过程中，高度的可塑性使得 神经元进行精确而有功能的连接。这种可塑性在成年人身上会下降， 损害神经系统修复损伤和恢复功能的能力。具体的 家长研究的目标是确定轴突背后的细胞和分子机制 以早期开发为目标，并确定控制关键时期的机制 老鼠的嗅觉系统。本附录将把研究扩展到APP的功能和 β42，以了解干扰发育可塑性的病理条件。

Project Summary Alzheimer’s Disease (AD) has devastating consequences on an individual’s wellbeing, community and society. The root cause of AD has not been clearly elucidated. The amyloid protein Aβ42 has been associated with AD pathology in form amyloid plaques that are thought to cause neuronal death in Alzheimer’s patients. Intensive research has identified the α-, β and γ- secretases as processing enzymes that process the amyloid precursor protein (APP) to produce soluble forms of APP, Aβ proteins and intracellular signaling domains. However, how APP processing is controlled and modulated by other proteins, and how different forms of the APP proteolytic product function, remains unclear. In this supplemental application, we propose to identify the interaction partners of APP, a mutant and pathogenic form of APP, and their cleavage products, to elucidate pathways involved in the trafficking and processing of APP, and the function of various proteolytic products under normal and pathological conditions. We will utilize APEX2 fusion proteins, a novel approach to allow extremely accurate labeling of closely associated protein to achieve this goal. We will conduct this set of experiments in the mouse olfactory system. In Alzheimer’s disease, olfactory dysfunction is one of the earliest manifestations of pathology. Expression of mutant forms of APP causes dramatic alteration of axon projection patterns and synaptic connections. The physical separation of the olfactory sensory neurons and their axons in different compartments make it an easily accessible system to dissociate protein functions in the axons from those in the cell body. This study will provide much needed in vivo examination of pathways that process and interact with APP. This study is relevant to the parent grant. The main goal of the parent grant is to understand the cellular and molecular mechanisms of the development plasticity that permit precise neuronal connections in the brain. During early postnatal brain development, a high level of plasticity allows the neurons to make precise and functional connections. This plasticity declines in the adults, impairing the ability of the nervous system to repair damages and restore function. The specific goals of the parent study are to identify the cellular and molecular mechanisms underlying axon targeting in early development and to identify the mechanism that controls the critical period in the mouse olfactory system. This supplement will extend the study to the function of APP and Aβ42 to understand pathological conditions that interfere with developmental plasticity.