A Model for Olfactory Epithelial Neurodegeneration in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）的病因非常复杂，遗传和环境因素都有牵连。长期以来，人们一直认为嗅觉缺陷先于痴呆症的临床症状，嗅觉结构表现出与中枢神经系统相似的病理症状。然而，为什么嗅觉系统特别容易受到影响尚不清楚。我们提供了一种新的模型来研究阿尔茨海默病在嗅觉系统中的神经退行性变。我们证明Notch2受体在维持嗅觉上皮正常神经胶质功能中起关键作用。在缺乏Notch2的情况下，神经胶质功能逐渐受损，最终导致成年动物的神经变性。胶质细胞在支持神经元存活方面发挥着许多作用，包括改善和潜在地加剧氧化应激。阿尔茨海默病的一个中心假设是氧化应激在神经退行性变中的作用。我们将在体内和体外研究Notch2在调节胶质细胞对氧化应激反应中的作用。了解Notch2信号的改变如何导致神经退行性变，对于理解阿尔茨海默病中神经元存活如何受到影响具有重要意义。公共卫生相关性：该项目旨在深入了解阿尔茨海默病的神经变性是如何发展的。我们特别关注嗅觉系统，并使用分子遗传学方法来解剖Notch通路在变性中的作用。

DESCRIPTION (provided by applicant): The etiology of Alzheimer's disease (AD) is highly complex, and both genetic and environmental factors have been implicated. Olfactory deficits have long been known to precede clinical signs of dementia, and olfactory structures show similar signs of pathology as those in the CNS. However, why the olfactory system is particularly susceptible is not known. Here we provide a novel model to study neurodegeneration in AD within the olfactory system. We demonstrate that the Notch2 receptor plays a key role in maintaining normal glial function in the olfactory epithelium. In the absence of Notch2, glial function is progressively compromised, ultimately leading to neurodegeneration in adult animals. Glia serve many roles in supporting neuronal survival, including ameliorating and potentially exacerbating oxidative stress. A central hypothesis in AD is the role of oxidative stress upon neurodegeneration. We will study the effects of Notch2 upon regulation of glial response to oxidative stress in vivo and in vitro. Understanding how altered Notch2 signaling leads to neurodegeneration has important implications for understanding how neuronal survival is affected in AD. PUBLIC HEALTH RELEVANCE: This project aims to provide insight into how neurodegeneration develops in Alzheimer's disease. We focus specifically on the olfactory system, and use a molecular genetic approach towards dissecting the role of the Notch pathway in degeneration.