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。 公共卫生相关性： 衰老是与阿尔茨海默病(AD)相关的最重要的危险因素。退伍军人构成了人口中越来越年长的部分，因此越来越有可能患上这种令人衰弱的疾病。目前，AD患者的临床选择有限。使这一问题复杂化的是越来越多令人失望的临床试验结果，这些结果共同突显了开发关于潜在治疗策略的新想法的重要性，以及确定新治疗靶点的必要性。从临床角度来看，有证据表明，抑制过度的谷氨酸刺激有助于治疗阿尔茨海默病。谷氨酸是一种正常的神经递质，脑细胞用来相互交流。然而，如果谷氨酸不被迅速去除，它就会变得有毒。谷氨酸转运体GLT-1(也称为EAAT2)清除过量的谷氨酸，从而防止它损害脑细胞。从病理学的角度来看，有证据表明GLT-1在AD中减少，并被积累在AD大脑中的其他称为A的有毒分子破坏。该项目建议使用一种新的AD动物模型，该模型将测试GLT-1功能障碍在AD中的重要性，并帮助确定增加GLT-1是否可能是一种良好的候选治疗方法。此外，我们将尝试确定GLT-1在人类AD患者中是如何受损的。这个项目的目标的成功完成很可能是找到治疗或延迟AD的新方法的重要的第一步。

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. PUBLIC HEALTH RELEVANCE: Aging is the most significant risk factor associated with Alzheimer's disease (AD). Veterans make up an increasingly older segment of the population and thus are increasingly at risk of developing this debilitating disorder. Currently, there are limited clinical options for AD patients. Compounding this problem is the growing number of disappointing clinical trial results that collectively highlight the importance of developing new ideas about potential treatment strategies and the need to identify new therapeutic targets. From a clinical perspective there is evidence to suggest curbing excessive glutamate stimulation is helpful in treating AD. Glutamate is a normal neurotransmitter that brain cells use to communicate with each other. However, if glutamate is not quickly removed it becomes toxic. The glutamate transporter, GLT-1 (also called EAAT2) clears excess glutamate and thus prevents it from damaging brain cells. From a pathological perspective there is evidence that GLT-1 is reduced in AD and also damaged by other toxic molecules called A¿ that accumulate in AD brains. This project proposes to use a novel animal model of AD that will test the importance of GLT-1 dysfunction in AD and help determine whether increasing GLT-1 could be a good candidate therapeutic approach. In addition we will attempt to determine how GLT-1 becomes damaged in human AD patients. Successful completion of the aims of this project will likely be an important first step toward finding new ways to treat or delay AD.