TRANSMITTER NEUROANATOMY IN ALZHEIMERS DISEASE

阿尔茨海默病的递质神经解剖学

• 批准号: 6137032
• 负责人: David M. Armstrong
• 金额: $ 33.56万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137032
• 关键词: AMPA receptors; Alzheimer's disease; NMDA receptors; brain mapping; cytotoxicity; hippocampus; human tissue; immunocytochemistry; in situ hybridization; neural degeneration; neurotoxicology; protein localization; receptor expression; western blottings

DESCRIPTION (Applicant's Abstract): The proposed studies will address the issue of selective vulnerability of neurons in Alzheimer's disease. Underlying these studies is the hypothesis that excitotoxicity, particularly that which is mediated via stimulation of ionotropic glutamate receptors, contributes to the neuro-degeneration of Alzheimer's disease. Moreover, we predict that in Alzheimer's disease the perturbation of specific glutamate receptor subunits, particularly those involved in the gating of calcium, may contribute significantly to the viability of the cell. The current investigation focuses on the N-methyl- D-aspartate (NMDA) receptor. Notably, previous work of ours has focused on the distribution and expression of specific non-NMDA (i.e. AMPA) receptor subunits in the hippocampus of patients with Alzheimer's disease pathology. Collectively, these investigations attempt to provide a comprehensive understanding of the anatomy of the ionotropic glutamate receptor in the hippocampus of normal subjects and in subjects with Alzheimer's disease. In this application, we propose a series of highly correlated immunohistochemical (Specific Aims 1&2), biochemical (Specific Aim 3) and in situ hybridization studies investigating the distribution and level of expression of specific NMDA receptor subunits (e.g., NMDAR1, NR2A, NR2B, & NR2D). Studies will focus on the human hippocampus, in part, because this region is known to be affected very early within the progression of the disease. Subjects representing a broad range of neuropathologic severity (i.e. Braak stages I-VI) will be studied thus providing us with the opportunity of examining alterations in glutamate receptor expression throughout various stages of the disease. Moreover, the use of specific antibodies identifying early events in the evolution of neurofibrillary pathology provides an additional opportunity of correlating alterations in NMDA receptor subunit expression with initiating events of neurodegeneration. An understanding of the anatomical organization of NMDA and AMPA receptors and the mechanism underlying glutamate-mediated excitotoxicity is important before appropriate drugs aimed at halting Alzheimer's disease-associated neuronal degeneration can be developed.

描述（申请人的摘要）：拟议的研究将解决 阿尔茨海默病中神经元选择性脆弱性的问题。 这些研究的基础是兴奋性毒性，特别是 通过刺激离子型谷氨酸受体介导的， 导致阿尔茨海默病的神经变性。 此外，我们 预测在阿尔茨海默病中特定谷氨酸的扰动 受体亚基，特别是那些参与钙门控的亚基，可能 对细胞的活力有显着贡献。 目前的 研究重点是 N-甲基-D-天冬氨酸 (NMDA) 受体。 值得注意的是，我们之前的工作重点是分布和 特定非 NMDA（即 AMPA）受体亚基的表达 阿尔茨海默病患者的海马体病理学。 总的来说， 这些调查试图全面了解 正常人海马离子型谷氨酸受体的解剖 受试者和患有阿尔茨海默病的受试者。 在此应用中，我们提出了一系列高度相关的 免疫组织化学（具体目标 1 和 2）、生物化学（具体目标 3）和 原位杂交研究调查了分布和水平 特定 NMDA 受体亚基的表达（例如 NMDAR1、NR2A、NR2B 和 NR2D）。 研究将集中在人类海马体上，部分原因是 据了解，该地区在疫情进展的早期就受到了影响 疾病。 代表广泛神经病理学严重程度的受试者 （即布拉克阶段 I-VI）将被研究，从而为我们提供 检查谷氨酸受体表达变化的机会 贯穿疾病的各个阶段。 此外，使用特定的 识别神经原纤维进化早期事件的抗体 病理学提供了关联变化的额外机会 NMDA 受体亚基表达与起始事件 神经变性。 了解 NMDA 和 AMPA 受体的解剖结构 谷氨酸介导的兴奋性毒性的机制很重要 在采取适当的药物来阻止与阿尔茨海默氏病相关的疾病之前 可发生神经元变性。