GLUTAMATE RECEPTORS IN AGED RATS AND HUMAN ALZHEIMER'S DISEASE

与阿尔茨海默病相关的最戏剧性症状之一 (AD)并且，随着年龄的增长，在较小程度上是逐渐损害 学习和记忆。这种损害在一定程度上是由于 几个大脑结构中的斑块和缠结，包括大脑 大脑皮层和海马区，以及选择性退行性变 脆弱的神经细胞群体。尽管涉及的机制 与衰老和阿尔茨海默病相关的神经病理尚不清楚，但广泛存在 接受谷氨酸能传递的改变可能起作用 在学习障碍和神经元死亡中的关键作用。此视图 已经得到了大量研究的支持，这些研究表明 学习记忆和神经元中的谷氨酸受体 退化。我们之前的工作揭示了几个 调节氟他胺受体和HAS特性的机制 记录了这些机制在学习和记忆以及 成年大鼠脑内神经元变性。建议进行的研究包括 旨在将这些研究扩展到衰老的大鼠脑和从 并检验与谷氨酸变化相关的几个假说 受体和/或在调节其特性的机制中 老年大鼠突触可塑性和兴奋性毒性的变化。可能的 阿尔茨海默病患者脑内谷氨酸受体特性的改变及其调控 也将接受评估。具体目标如下：(一) 测定谷氨酸受体的性质和调节的变化 在老化的大鼠脑和人类AD中，(2)研究 衰老大鼠脑内谷氨酸能传递的调控机制 人类阿尔茨海默病，(3)评估连接机制的潜在变化 谷氨酸受体与衰老大鼠脑内神经元变性 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的潜在相关性 AD患者的严重程度。这项研究将使用各种分子 和生化技术研究幼年和老年大鼠的特性 以及阿尔茨海默病患者的大脑样本。它还将在体外使用 和体内突触可塑性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体内的特性。 这些研究将提供有关 谷氨酸能神经递质的增龄修饰机制 传播并确定关键步骤，以说明 在衰老和阿尔茨海默病中观察到学习障碍和神经元损伤。他们 因此可能会为设计最佳战略提供新的途径 缓解学习障碍，防止神经元损伤 与这些状态相关联。

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.