Glutamate dyshomeostasis: The role of glutamate transport dysfunction in Alzheim

描述(由申请人提供)： 谷氨酸转运体GLT-1(在人类组织中通常被称为EAAT2)清除大脑皮质和海马区的大部分谷氨酸，这是大脑中受阿尔茨海默病严重影响的区域。大量数据显示AD患者GLT-1/EAAT2基因表达降低和/或受损。然而，尽管GLT-1在大脑中具有关键的神经保护功能，但目前尚不清楚GLT-1缺失是否会显著导致与AD相关的认知症状或病理。解决这些关键问题受到以下因素的限制：(I)缺乏合适的动物模型来研究GLT-1功能障碍在AD相关病理中的生物学意义；以及(Ii)相对缺乏研究AD早期阶段GLT-1功能障碍的研究，从而削弱了我们理解GLT-1功能障碍与疾病进展相关的能力。为了解决这些重要问题，我们将APPswe/PS1(E9)小鼠与缺乏GLT-1等位基因的小鼠杂交，以产生一种新的AD动物模型，使我们能够开始在AD相关病理的背景下研究GLT-1缺失的后果。我们已经获得的数据表明，GLT-1的部分缺失扰乱了空间记忆，改变了A？(A)的积累。我们还获得了新的证据，表明EAAT2在AD的前驱和晚期都有异常表达。利用部分缺失GLT-1的APPswe/PS1(E9)小鼠，我们建议研究GLT-1功能障碍与突变型APP/PS1相互作用扰乱认知的机制。我们还建议通过确定AD患者中GLT-1的早期发生、病理相关的氧化后翻译后修饰来扩展我们对AD患者EAAT2功能障碍的理解。这些研究的成功完成将增加我们对大脑初级谷氨酸清除系统的损伤如何参与AD发病机制的理解，并可能为寻找针对大脑中这种重要神经递质的治疗策略提供新的工具。

DESCRIPTION (provided by applicant): 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¿ (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.