GLUTAMATE RECEPTORS IN AGED RATS AND HUMAN ALZHEIMER'S DISEASE

老年大鼠和人类阿尔茨海默病中的谷氨酸受体

• 批准号: 6234079
• 负责人: MICHEL BAUDRY
• 金额: $ 24.05万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-15 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234079
• 关键词: Alzheimer's disease; aging; aminoacid transport; autoradiography; brain metabolism; electroencephalography; gene induction /repression; glutamate receptor; hippocampus; human tissue; immunocytochemistry; in situ hybridization; laboratory rat; lipid metabolism; memory disorders; neural degeneration; neural plasticity; neural transmission; neuropharmacology; neurotransmitter transport; phosphatidylinositols; polyamines; protein biosynthesis; receptor binding; receptor expression

One of the most dramatic symptoms associated with Alzheimer's disease (AD) and, to a lesser extent, with aging, is a gradual impairment in learning and memory. This impairment is in part due to the presence of plaques and tangles in several brain structures, including the cerebral cortex and the hippocampus, as well as to the degeneration of selectively vulnerable neuronal populations. Although the mechanisms involved in the neuropathologies associated with aging and AD are not known, it is widely accepted that alterations in glutamatergic transmission might play critical roles in both learning impairment and neuronal death. This view has been supported by numerous studies indicating the participation of glutamate receptors in both learning and memory and in neuronal degeneration. Our previous work has revealed the existence of several mechanisms regulating the properties of flutamate receptors and has documented the roe of these mechanisms in learning and memory and in neuronal degeneration in adult rat brain. The proposed studies are intended to expand these studies to the aging rat brain and to brain from AD patients and to test several hypotheses relating changes in glutamate receptors and /or in mechanisms regulating their characteristics to changes in synaptic plasticity and excitotoxicity in aged rats. Possible alterations in glutamate receptor properties and regulation in AD brain will also be evaluated. The following specific aims will be pursued: (1) to determine the changes in glutamate receptor properties and regulation in aging rat brain and human AD, (2) to study potential changes in mechanisms regulating glutamatergic transmission in aging rat brain and human AD, (3) to evaluate potential changes in the mechanisms linking glutamate receptors and neuronal degeneration in aging rat brain, and (4) in view of the regulation of the NMDA receptor by polyamines, to study potential correlation between CSF and blood polyamine levels and disease severity in AD patients. The research will use a variety of molecular and biochemical techniques to study the properties in young and old rats as well as in brain samples from AD patients. It will also use in vitro and in vivo models of synaptic plasticity to study mechanisms regulating glutamate receptors, glutamatergic transmission, and the excitotoxic properties of glutamate in young and old rats. These studies will provide important information concerning the mechanisms involved in age-related modifications of glutamatergic transmission and identify critical steps that could account for the learning deficits and neuronal damage observed with aging and AD. They might therefore suggest new avenues for designing optimal strategies to alleviate the learning deficits and to prevent the neuronal damage associated with these states.

与阿尔茨海默病相关的最显着的症状之一 （AD），并且在较小程度上，随着年龄的增长， 学习和记忆。 这种损害部分是由于存在 多个大脑结构中的斑块和缠结，包括大脑 皮质和海马体，以及选择性退化 脆弱的神经元群体。 尽管涉及的机制 与衰老和 AD 相关的神经病理学尚不清楚，但广泛 承认谷氨酸传输的改变可能发挥作用 在学习障碍和神经元死亡中发挥关键作用。 这个观点 已得到大量研究的支持，表明参与 学习和记忆以及神经元中的谷氨酸受体 退化。 我们之前的工作已经揭示了几个问题的存在 调节氟胺酸受体特性的机制 记录了这些机制在学习和记忆中的作用 成年大鼠大脑中的神经元变性。 拟议的研究是 旨在将这些研究扩展到衰老大鼠的大脑和来自 AD 患者并测试与谷氨酸变化相关的几个假设 受体和/或调节其特征的机制 老年大鼠突触可塑性和兴奋毒性的变化。 可能的 AD 大脑中谷氨酸受体特性和调节的改变 也将被评估。 将追求以下具体目标：（1） 确定谷氨酸受体特性和调节的变化 在衰老大鼠大脑和人类 AD 中，(2) 研究 调节衰老大鼠大脑谷氨酸能传递的机制 人类 AD，（3）评估连接机制的潜在变化 衰老大鼠大脑中的谷氨酸受体和神经元变性，以及（4） 鉴于多胺对NMDA受体的调节作用，研究 脑脊液和血液多胺水平与疾病之间的潜在相关性 AD 患者的严重程度。 该研究将使用多种分子 和生化技术来研究年轻和年老大鼠的特性 以及 AD 患者的大脑样本中。 它还将在体外使用 和突触可塑性的体内模型来研究调节机制 谷氨酸受体、谷氨酸能传递和兴奋性毒性 谷氨酸在幼年和老年大鼠中的特性。 这些研究将提供有关 与年龄相关的谷氨酸能修饰有关的机制 传输并确定可以解释的关键步骤 随衰老和 AD 观察到的学习缺陷和神经元损伤。 他们 因此可能会提出设计最佳策略的新途径 缓解学习缺陷并防止神经元损伤 与这些状态相关。