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: 6168030
• 负责人: JOHN H MORRISON
• 金额: $ 35.16万
• 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/6168030
• 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 我们缺乏将涉及分子的数据，例如谷氨酸 受体（glurs），在容易发生的神经回路的背景下 与年龄相关的功能折衷或变性。 我们的主要目标是 在特定gl和钥匙皮层之间建立精确的联系 和HipooCampal电路。 我们还将定义与年龄有关的病变 - 诱导高水平胶水分布的变化 和电路特异性。 这样的分析都将阐明受体 兴奋回路的多样性，并揭示了Glur曲线 与正常衰老和阿尔茨海默氏病的脆弱性有关。 那里 是四个组成部分： 1）生产必要的试剂。 我们制作的计划和 表征亚基特异性单克隆抗体（mAb）to glurs 继续，最高的优先级是mab的发展 区分所有AMPA和Kainate亚基（即Glur1-7和Ka1,2），以及 亚基NMDAR2 A-D。 ii）兴奋回路的受体编码。 我们假设 收敛兴奋性电路将在其Glur中表现出特殊性 配置文件，Glur配置文件将直接相关 给定电路的功能作用和相对脆弱性。 这 Glur曲线中的特异性将主要在 可以等同的单个树突段，刺和突触 带有确定的传入传入。 为了测试这一点，Glur分布 海马和视觉皮层将在高分辨率下以 在确定的电路的背景下增加了亚基特异性 这两者都在其功能属性和脆弱性中 退化。 iii）衰老的影响。 我们假设与年龄相关的障碍 可以通过特定的glur亚基的细微变化来介导 结构完整的电路。 我们已经描述了NMDA特定的 树突状段的改变，将穿孔路径输入扩散到 发生在老年灵长类动物中的齿状回。 我们将追求这个 用亚基特异性抗体和高分辨率神经解剖学发现 确定其特异性和程度的技术 没有对电路的结构损害。 iv）破坏后gl的电路特异性偏移。 我们有 假设通过破坏穿孔路径的剥夺将 还会导致齿状回的胶状变化，但这些变化将是 多方面的结构和分子变化让人联想到AD。 在 对比度，功能性脱落可能会导致Glur变化更多 让人联想到正常衰老。 ERC的年轻猴子和老鼠将 从电解或功能上与 带有TTX注射的齿状回测试该假设。 病变 - 诱导的Glur表达变化将相对于时间分析 效果，家庭和亚基特异性，相对贡献 分子与结构的突触后反应以及依赖性 对年龄的影响。