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: 8195897
• 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/8195897
• 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

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.

项目总结/摘要 谷氨酸转运蛋白GLT-1（在人体组织中通常称为EAAT 2）清除了大部分的谷氨酸。 谷氨酸在大脑皮层和海马区，这是严重影响AD。一 大量数据显示，AD患者中GLT-1/EAAT 2减少和/或受损。 尽管如此，尽管GLT-1在大脑中具有重要的神经保护功能，但目前尚不清楚GLT-1是否在大脑中起作用。 这种损失显著地促成与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）缺乏可以使用的适当动物模型， 检查GLT-1功能障碍在AD相关病理学中的生物学意义;和（ii） 相对缺乏研究解决GLT-1功能障碍的早期阶段的AD，从而削弱了我们的研究。 了解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 â E9小鼠与缺乏APPswe/PS1 â E9的小鼠进行了杂交 GLT-1的一个等位基因，以产生一种新的AD动物模型，使我们能够开始检查 在AD相关病理学背景下GLT-1缺失的后果。我们得到了数据 这表明GLT-1的部分缺失扰乱了空间记忆并改变了A-β（A？）的积累。 我们还获得了新的证据，表明EAAT 2在两种细胞中表达异常， 前驱期和晚期AD。 使用GLT-1部分缺失的APPswe/PS1 <$E9小鼠，我们建议研究 GLT-1功能障碍与突变型APP/PS1相互作用以干扰认知的机制。我们 我还建议通过早期识别AD患者的EAAT 2功能障碍来扩展我们对AD患者EAAT 2功能障碍的理解。 AD中GLT-1发生的病理学相关的氧化翻译后修饰。 这些研究的成功完成将增加我们对如何损害 大脑的主要谷氨酸清除系统参与AD发病机制，并可能提供 新的工具，以促进寻找治疗策略，针对这一重要的神经递质 在大脑中。