Project 3: Immune Markers Linking Pathogenesis in Animal Models and Human Neurodegenerative Disease

项目摘要/摘要 阿尔茨海默病(AD)是一种神经退行性疾病，其特征是进行性丧失 记忆。AD的病理特征包括淀粉样β蛋白(A�)斑块沉积、神经原纤维缠结 (NFT)的形成和突触和神经元的进行性丧失。越来越多的文献表明 大脑中的免疫激活，特别是激活的小胶质细胞可能通过以下方式促进AD的进展 促进A�沉积和NFT。这些发现与AD的几个危险因素的识别很好地吻合 与免疫和炎症途径有关。单独的数据表明，内生的 神经递质GABA具有调节小胶质细胞活化和免疫功能的作用。这个 识别AD免疫激活的调节机制可能会提供有价值的见解 研究疾病进展以及确定新的治疗靶点。 项目3将确定GABA递质系统的变化可能涉及的程度 在阿尔茨海默病的免疫激活中。我们将确定GABA信号的变化是否与行为有关 阿尔茨海默病动物模型的脑损伤和病理改变(A�，NFT)。我们将进一步 评估特定GABA受体缺失对AD动物模型小胶质细胞的影响 如果AD的免疫反应发生改变。最后，我们建议确定特定GABA的损失是否 小胶质细胞上的受体加剧了与阿尔茨海默病一致的行为和病理缺陷。这些数据可能 为解决免疫激活和AD进展的机制提供宝贵的信息。

Project Summary/Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory. Pathological hallmarks of AD include amyloid-beta (A�) plaque deposition, neurofibrillary tangle (NFT) formation and the progressive loss of synapses and neurons. A growing literature has indicated that immune activation in the brain, in particular activated microglia may contribute to the progression of AD by facilitating A� deposition and NFTs. These findings fit well with the identification of several risk factors in AD are associated with immune and inflammatory pathways. Separate data indicate the endogenous neurotransmitter GABA is capable of modulating activation of microglia and immune function. The identification of mechanisms involved in modulating immune activation in AD may provide valuable insight into disease progression as well as identify novel therapeutic targets. Project 3 will determine the extent to which changes in the GABA transmitter system may be involved in immune activation in AD. We will determine if changes in GABA signaling are related to behavioral impairments and pathological changes in the brain (A�, NFT) in an animal model of AD. We will further evaluate the impact of the loss of a specific GABA receptor on microglia in the AD animal model to determine if the immune response in AD is altered. Lastly, we propose to determine if the loss of a specific GABA receptor on microglia exacerbates behavioral and pathological deficits consistent with AD. These data may provide invaluable information for a mechanism to addresses immune activation and the progression of AD.