Glutamate dyshomeostasis: The role of glutamate transport dysfunction in Alzheim

项目摘要/摘要 谷氨酸转运体GLT-1(在人体组织中通常被称为EAAT2)清除了大部分 大脑皮质和海马体中的谷氨酸--大脑中受阿尔茨海默病严重影响的区域。一个 大量数据表明，AD患者GLT-1/EAAT2基因表达降低和/或受损。 尽管如此，尽管GLT-1在大脑中具有关键的神经保护功能，但尚不清楚GLT-1是否 失落对与AD相关的认知症状或病理有很大影响。寻址 这些关键问题受到以下因素的限制：(1)缺乏可以使用的适当动物模型 探讨GLT-1功能障碍在AD相关病理中的生物学意义；及 相对缺乏关于AD早期阶段GLT-1功能障碍的研究，因此损害了我们的 能够理解GLT-1功能障碍与疾病进展的关系。 为了解决这些重要问题，我们将APPswe/PS1？E9小鼠与缺乏 GLT-1的一个等位基因产生了一种新的AD动物模型，使我们能够开始研究 GLT-1缺失在AD相关病理背景下的后果。我们已经获得了数据 提示GLT-1的部分缺失扰乱了空间记忆，改变了A-β(A？)的积累。 我们还获得了新的证据，表明EAAT2在这两个组织中都有异常表达 前驱症状和晚期AD。 利用部分缺失GLT-1的APPswe/PS1？E9小鼠，我们建议研究 GLT-1功能障碍与突变的APP/PS1相互作用扰乱认知的机制。我们 还建议通过早期识别AD患者的EAAT2功能障碍来扩展我们对其功能障碍的理解 阿尔茨海默病患者GLT-1发生的、病理上相关的氧化后修饰。 这些研究的成功完成将增加我们对 大脑的初级谷氨酸清除系统参与了AD的发病，并可能为 促进寻找针对这种重要神经递质的治疗策略的新工具 在大脑里。

Project Summary/Abstract The glutamate transporter GLT-1 (often called EAAT2 in human tissue) clears much of the glutamate in the cortex and hippocampus-regions of the brain that are heavily affected by AD. A significant body of data shows that GLT-1/EAAT2 is reduced and/or damaged in AD patients. Nonetheless, despite its critical neuroprotective functions in the brain, it is not known whether GLT-1 loss contributes significantly to the cognitive symptoms or pathology associated with AD. Addressing these key issues has been limited by: (i) the lack of an appropriate animal model that could be used to examine the biological significance of GLT-1 dysfunction in AD-related pathology; and (ii) the relative paucity of studies addressing GLT-1 dysfunction in the early stages of AD, thus impairing our ability to understand how GLT-1 dysfunction relates to the disease progression. To address these important issues we have crossed APPswe/PS1¿E9 mice with mice lacking one allele of GLT-1 to produce a novel animal model of AD that has allowed us to begin examining the consequences of GLT-1 loss in the context of AD-related pathology. We have obtained data suggesting that partial loss of GLT-1 disturbs spatial memory and alters A-beta (A¿) accumulation. We have also obtained new evidence suggesting that EAAT2 is aberrantly expressed in both prodromal and later-stage AD. Using APPswe/PS1¿E9 mice with partial loss of GLT-1 we propose to investigate the mechanisms by which GLT-1 dysfunction interacts with mutant APP/PS1 to disturb cognition. We also propose to extend our understanding of EAAT2 dysfunction in AD patients by identifying early occurring, pathologically relevant oxidative post-translational modifications of GLT-1 in AD. Successful completion of these studies will increase our understanding of how damage to the primary glutamate clearance system of the brain is involved in AD pathogenesis and may provide new tools to facilitate the search for therapeutic strategies that target this important neurotransmitter in the brain.