MENTAL ILLNESS IN ALZHEIMERS DISEASE OF THE AGED

老年痴呆症中的精神疾病

• 批准号: 2244726
• 负责人: CAROL A MILLER
• 金额: $ 34.08万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2244726
• 关键词: Alzheimer's disease; aging; behavior disorders; brain disorder diagnosis; brain mapping; caudate nucleus; cognition disorders; dementia; fluorescence microscopy; genetic manipulation; hearing disorders; hippocampus; histopathology; human subject; immunocytochemistry; longitudinal human study; memory disorders; molecular pathology; monoclonal antibody; neocortex; neural degeneration; neuropsychological tests; neurotransmitters; nucleic acid probes; optic nerve disorder; postmortem; putamen; retinal ganglion; southern blotting; subtraction hybridization; vision disorders

Neuronal degeneration is a major histopathologic finding in Alzheimer's disease (AD). Selective vulnerability of subpopulations of subcortical neurons has previously been described. We recently described retinal ganglion cell loss and optic neuropathy, all in the absence of neuritic plaques, neurofibrillary tangles and amyloid angiopathy. Clinically, some AD patients show changes in visual evoked responses. Although the CNS contains heterogeneous cell populations, a monoclonal antibody marker (MAb 3F12) has identified some of the vulnerable neurons in the neocortex, hippocampus, and possibly the axons of retinal ganglion cells undergoing degeneration. Little is known of the molecular specificities of these cells in normal or AD brain or retina. IN this study we propose to analyze neuronal-specific function at three levels: clinical, histologic, and molecular. For the clinical studies we shall focus on the visual system, integrating the neurologic and psychometric database with specific visual function studies. Patients will be followed to autopsy and retinal ganglion cell loss assessed. A parallel histologic assessment of auditory system neuronal changes will be made. Temporal progression of neuronal loss in AD will be examined. With use of neuron-specific monoclonal probes, the architectonic differences in neuronal changes in AD will also be compared to other dementing diseases (Pick's, Parkinson's). The AD-vulnerable neurons will be further defined by: (1) immunocytochemical identification of their associated neurotransmitter and neuropeptides, (2) molecular characterization of Ag3F12, and (3) development of a neuron-enriched cDNA library. MAb 3F12 will be used to isolate clones from a human brain cDNA expression library, localization confirmed by combined in situ hybridization and immunoperoxidase staining. Isolated 3F12 cDNA clones will be useful as markers of pyramidal cell enrichment in preparation of a new neuron-enriched cDNA library. To enhance isolation of rare or low abundance mRNA species, we shall use subtraction hybridization methods. Transcripts will be screened by Northern and Southern blot analyses, and positives by in situ hybridization in normal and AD neocortex, hippocampus and retina. Proteins and/or transcripts of interest will be sequenced to determine if they are of known molecular specificity. Development of this neuronal subset-specific molecular panel may contribute to the understanding of regulatory mechanisms operative in these cells in AD.

神经元变性是阿尔茨海默氏症的主要组织病理学发现 疾病（AD）。 皮层亚群的选择性脆弱性 神经元以前已经描述过。 我们最近描述了视网膜 神经节细胞丧失和视神经病变，所有这些都没有神经性 斑块，神经原纤维缠结和淀粉样血管病。 临床上 一些AD患者显示出视觉诱发反应的变化。 虽然 中枢神经系统包含异质细胞群，一种单克隆抗体 标记（mAb 3f12）已经确定了一些脆弱的神经元 新皮层，海马，可能是视网膜神经节细胞的轴突 进行变性。 分子知之甚少 这些细胞在正常或AD脑或视网膜中的特异性。 在这个 研究我们建议分析三个级别的神经元特异性功能： 临床，组织学和分子。 对于临床研究，我们将 关注视觉系统，整合神经系统和心理测量 具有特定视觉功能研究的数据库。 患者会 随后评估了尸检和视网膜神经节细胞损失。 平行 将对听觉系统神经元变化进行组织学评估。 将检查AD中神经元丧失的时间进展。 使用 神经元特异性的单克隆探针的结构差异 AD的神经元变化也将与其他痴呆疾病进行比较 （Pick's，帕金森氏症）。 可广泛的神经元将进一步定义：（1） 其相关神经递质的免疫细胞化学鉴定 和神经肽，（2）AG3F12的分子表征和（3） 富含神经元的cDNA文库的开发。 MAB 3F12将用于 分离人脑cDNA表达文库的克隆，定位 通过原位杂交和免疫过氧化物酶确认 染色。 孤立的3F12 cDNA克隆将作为标记有用 锥体细胞富集在制备新的神经元增强的cDNA中 图书馆。 为了增强稀有或低丰度mRNA物种的分离，我们 应使用减法杂交方法。 成绩单将是 由北部和南部印迹分析进行筛选，并由 正常和新皮层，海马和视网膜的原位杂交。 蛋白质和/或感兴趣的成绩单将被测序以确定 如果它们具有已知的分子特异性。 发展的发展 神经元亚集特异性分子面板可能有助于 了解AD中这些细胞中操作的调节机制。