Glutamate dyshomeostasis: The role of glutamate transport dysfunction in Alzheim

谷氨酸稳态失调：谷氨酸转运功能障碍在阿尔茨海默病中的作用

• 批准号: 7796986
• 负责人: David G Cook
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796986
• 关键词: APP-PS1; Accounting; Address; Affect; Aging; Alleles; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animal Model; Astrocytes; Biological; Brain; Brain region; Clinical; Clinical Trials; Cognition; Cognitive; Data; Disease; Disease Progression; Family; Functional disorder; Glutamate Transporter; Glutamates; Hippocampus (Brain); Human; Light; Memantine; Memory; Modeling; Mus; Neurobehavioral Manifestations; Neuronal Plasticity; Neurotransmitters; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Play; Population; Post-Translational Protein Processing; Presynaptic Terminals; Process; Property; Relative (related person); Risk; Risk Factors; Role; Staging; Synapses; System; Testing; Therapeutic; Veterans; adduct; brain cell; clinically relevant; excitotoxicity; familial Alzheimer disease; human tissue; mouse model; mutant; neurotransmission; new therapeutic target; novel; presenilin-1; prevent; public health relevance; tool; treatment strategy

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.

描述（由申请人提供）： 谷氨酸转运蛋白GLT-1（通常在人体组织中称为EAAT2）清除了大脑的皮质和海马区域中的大部分谷氨酸，这些谷氨酸受AD的影响很大。大量数据表明，AD患者的GLT-1/EAAT2降低和/或损坏。尽管如此，Dospite的关键神经保护功能在大脑中，GLT-1损失是否对与AD相关的认知症状或病理有显着贡献。解决这些关键问题的受到限制：（i）缺乏适当的动物模型，该模型可用于检查与AD相关病理学中GLT-1功能障碍的生物识别意义； （ii）在AD的早期阶段，针对GLT-1功能障碍的研究的相对匮乏，从而损害了我们了解GLT-1功能障碍与疾病进展的能力。为了解决这些重要问题，我们已经跨越了APPSWE/PS1（E9小鼠与缺乏GLT-1等位基因的小鼠来产生一种新型的AD动物模型，该模型使我们能够在AD相关病理学的背景下检查GLT-1损失的后果。我们已经获得了GLT-1损失的数据，这表明GLT-1损失的迹象表明，促进了空间记忆和Alters a aby a easuntion a Exulation a easuntion a easuntion ae easuntion。使用AppSwe/PS1（E9小鼠的GLT-1损失，我们建议使用GLT-1功能障碍与灾难认知与突变的APP/PS1相互作用。这些研究的成功完成将提高我们对大脑原发性谷氨酸清除系统的损害如何参与AD发病机理的理解，并可能提供新的工具，以促进寻找针对大脑中这种重要神经递质的治疗策略。 公共卫生相关性： 衰老是与阿尔茨海默氏病（AD）相关的最重要的危险因素。退伍军人构成了越来越大的人群，因此越来越有可能发展这种令人衰弱的疾病的风险。目前，广告患者的临床选择有限。使这个问题更加复杂的是，令人失望的临床试验结果越来越多，共同强调了开发有关潜在治疗策略的新想法的重要性以及确定新的治疗靶标的需求。从临床角度来看，有证据表明抑制过量的谷氨酸刺激有助于治疗AD。谷氨酸是一种正常的神经递质，脑细胞用来彼此通信。但是，如果没有迅速去除谷氨酸，则会有毒。谷氨酸转运蛋白GLT-1（也称为EAAT2）清除了多余的谷氨酸，从而防止其损坏脑细胞。从病理学的角度来看，有证据表明，GLT-1在AD中降低，并被累积在AD大脑中的其他有毒分子损坏。该项目的建议是使用一种新型的AD动物模型，该模型将测试GLT-1功能障碍在AD中的重要性，并有助于确定增加GLT-1是否可能是一种良好的候选治疗方法。此外，我们将尝试确定人类AD患者的GLT-1如何损坏。成功完成该项目的目标可能是寻找新方法来治疗或延迟广告的重要第一步。