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: 8391149
• 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/8391149
• 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.

描述（由申请人提供）：