CORTICO-CORTICAL LOSS IN ALZHEIMERS DISEASE IN THE AGED

老年人阿尔茨海默病的皮质-皮质损失

• 批准号: 2899732
• 负责人: JOHN H MORRISON
• 金额: $ 33.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2899732
• 关键词: Alzheimer's disease; Macaca mulatta; NMDA receptors; afferent nerve; aging; antireceptor antibody; chimeric proteins; dendrites; dentate gyrus; entorhinal cortex; experimental brain lesion; glutamate receptor; hippocampus; immunocytochemistry; laboratory rat; monoclonal antibody; neuroanatomy; receptor expression; synapses; tetrodotoxin; transfection; visual cortex; western blottings

Our understanding of selective vulnerability continues to be hampered by our lack of data that place implicated molecules, such as glutamate receptors (GluRs), in the context of the neural circuits that are prone to age-related functional compromise or degeneration. Our major goal will be to establish precise linkage between specific GluRs and key corticocortical and hipoocampal circuits. We will also define age-related and lesion- induced changes in the distribution of GluRs with a high level of subunit and circuit specificity. Such analyses will both clarify receptor diversity of excitatory circuits, and reveal the GluR profile that is related to vulnerability in normal aging and Alzheimer's Disease. There are four components: 1) Production of necessary reagents. Our program to produce and characterize subunit specific monoclonal antibodies (mAb) to GluRs will continue, with the highest priority being the development of mAbs that distinguish all AMPA and kainate subunits (i.e., GluR1-7, and KA1,2), and subunits NMDAR2 A-D. II) Receptor coding of excitatory circuits. We have hypothesized that convergent excitatory circuits will exhibit specificity in their GluR profile, and the GluR profile will be directly related to both the functional role and relative vulnerability of a given circuit. The specificity in GluR profile will be apparent primarily at the level of individual dendritic segments, spines, and synapses that can be equated with identified incoming afferents. To test this, GluR distribution in hippocampus and visual cortex will be characterized at high resolution with increased subunit specificity , and in the context of identified circuits that very both in their functional attributes and vulnerability to degeneration. III) Effects of Aging. We have hypothesized that age-related impairments may be mediated by subtle shifts in specific GluR subunits in otherwise structurally intact circuits. We have described an NMDA specific alteration in the dendritic segments subserving the perforant path input to the dentate gyrus that occurs in aged primates. We will pursue this finding with subunit specific antibodies and high resolution neuroanatomic techniques to determine its specificity and degree to which it occurs without structural damage to the circuit. IV) Circuit-specific shifts in GluRs following disruption. We have hypothesized that deafferentation by destruction of the perforant path will also cause changes in GluRs in the dentate gyrus, but these changes will be multi-faceted structural and molecular changes reminiscent of AD. In contrast, functional deafferentation might cause GluR changes more reminiscent of normal aging. ERC in young and aged monkeys and rats will be lesioned either electrolytically or functionally disconnected from the dentate gyrus with TTX injections to test this hypothesis. The lesion- induced changes in GluR expression will be analyzed with respect to time course of effects, family and subunit specificity, relative contribution of molecular vs structural postsynaptic responses, and dependence of the effect on age.

我们对选择性脆弱性的理解继续受到以下因素的阻碍： 我们缺乏相关分子的数据，例如谷氨酸 受体（GluR），在神经回路的背景下，容易 与年龄相关的功能损害或退化。 我们的主要目标将是 建立特定 GluR 与关键皮质之间的精确联系 和海马回路。 我们还将定义与年龄相关的和病变- 诱导高水平亚基 GluR 分布的变化 和电路的特殊性。 此类分析将阐明受体 兴奋性回路的多样性，并揭示了 GluR 的概况 与正常衰老和阿尔茨海默病的脆弱性有关。 那里 有四个组成部分： 1) 必要试剂的制作。 我们的计划是生产和 表征 GluR 的亚基特异性单克隆抗体 (mAb) 将 继续，最优先的是开发单克隆抗体 区分所有 AMPA 和红藻氨酸亚基（即 GluR1-7 和 KA1,2），以及 亚基 NMDAR2 A-D。 II) 兴奋性电路的受体编码。 我们假设 会聚兴奋回路将在其 GluR 中表现出特异性 配置文件，并且 GluR 配置文件将直接与 给定电路的功能作用和相对脆弱性。 这 GluR谱的特异性主要在以下水平上显而易见： 可以等同的单个树突片段、树突棘和突触 与已识别的传入传入。 为了测试这一点，GluR 分布在 海马体和视觉皮层将以高分辨率进行表征 增加亚基特异性，并在已识别的电路的背景下 这在它们的功能属性和脆弱性方面都非常重要 退化。 III) 衰老的影响。 我们假设与年龄相关的损伤 可能是由特定 GluR 亚基的微妙变化介导的 电路结构完好。 我们已经描述了 NMDA 特定的 树突片段的改变有助于穿通路径输入 老年灵长类动物的齿状回。 我们将追求这个 使用亚基特异性抗体和高分辨率神经解剖学发现 确定其特异性和发生程度的技术 不会对电路造成结构性损坏。 IV) 中断后 GluR 的电路特异性变化。 我们有 假设通过破坏穿通路径而导致传入阻滞 也会引起齿状回中 GluR 的变化，但这些变化将 多方面的结构和分子变化让人想起AD。 在 相比之下，功能性传入神经阻滞可能会导致 GluR 的变化更多 让人想起正常的衰老。 年轻和年老的猴子和大鼠中的 ERC 受到电解损伤或功能性断开 齿状回注射 TTX 来检验这一假设。 病变部位—— 将根据时间分析 GluR 表达的诱导变化 效应过程、家族和亚基特异性、相对贡献 分子与结构突触后反应，以及 对年龄的影响。