NEUROTROPHIC SUPPORT IN AGING & ALZHEIMER'S DISEASE

神经营养支持衰老

• 批准号: 3453172
• 负责人: FELIX P ECKENSTEIN
• 金额: $ 10.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3453172
• 关键词: Alzheimer's disease; Schwann cells; aging; astrocytes; axon; bioassay; brain cell; brain injury; cell differentiation; cell type; central nervous system; cerebral cortex; gene expression; glia; hippocampus; immunochemistry; innervation; laboratory rat; macromolecule; neural degeneration; neural information processing; neurons; neurotrophic factors; parasympathetic nervous system; prosencephalon; tissue /cell culture

The mechanisms regulating development and maintenace of the complex and specific innervation patterns characteristic for mammalian central nervous system remain poorly understood. Seveal independent observations, however, suggest that two different types of specific extracellular molecular signals play a major role in this process. The first type of signal are soluble neurotrophic factors that support the survival and differentiation of specific types of neurons, and the second type of signal is thought to consist of insoluble molecules that provide areas of selective adhesion to growing neurites. Identification and characterization of such molecular signals, as well as knowing how the expression of these molecules is regulated, are of central important for understanding of how innervation patterns develop and are maintained. It is of special interest to identify the role of such molecules in aging and to investigate whether interference with their action is involved in the etiology of neurodegenerative disorders, such as Alzheimer's disease (AD). This proposal describes a study focused on the identification of the cell types and molecules providing trophic signals to the cholinergic neurons in basal forebrain that innervate hippocampus and cerebral cortex. It will also be studied how the expression of neurotrophic support is regulated and what the role of such support in aging and AD. Previously, in collaboration with others, I have shown that Nerve Growth Factor (NGF) promotes differentiation in cholinergic basal forebrain neurons. Preliminary results suggest that NGF alone can not completely replace the trophic support derived from glial cells. In addition, I have recently obtained several monoclonal antibodies to antigens induced in specific classes of glial cells during injury-induced sprouting of the cholinergic innervation of hippocampus. The goals of this study are: - To determine what molecules support the survival and differentiation of cholinergic basal forebrain neurons. - To identify the cell type that produces such molecules. - To characterize whether specific classes of glial cells express additional trophic support when expressing the injury-induced antigens. - To study the molecular properties of the injury-induced antigens. - To investigate the levels and the regulation of expression of trophic support and the injury-induced antigens in aging and degenerative disease. Methods to be used include growing basal forebrain neurons in culture in the presence of known neurotrophic factors and tissue extracts; co-culturing of basal forebrain neurons with different types of feeder-layers and feeder-layer derived molecules; and biochemical and immunochemical characterization and purification of relevant molecules.

调节发育和维持的机制 复杂且特定的神经支配模式特征 哺乳动物的中枢神经系统仍然知之甚少。 然而，几项独立的观察结果表明，两个 不同类型的特定细胞外分子信号发挥着 在此过程中发挥重要作用。 第一类信号是可溶的 支持生存和分化的神经营养因子 特定类型的神经元，第二种类型的信号是 被认为由不溶性分子组成，提供区域 选择性粘附生长中的神经突。 识别和 这些分子信号的表征，以及了解 如何调节这些分子的表达是至关重要的 对于理解神经支配模式如何发展很重要 并得到维护。 确定以下角色的作用特别有意义： 这些分子在衰老过程中是否会受到干扰 它们的作用涉及神经退行性疾病的病因学 疾病，例如阿尔茨海默病（AD）。 该提案描述了一项专注于识别 向细胞提供营养信号的细胞类型和分子 基底前脑中支配海马体的胆碱能神经元 和大脑皮层。 还将研究如何表达 神经营养支持受到调节，其作用是什么 支持衰老和AD。 此前，与其他人合作， 我已经证明神经生长因子 (NGF) 可以促进 胆碱能基底前脑神经元的分化。 初步结果表明单独使用NGF并不能完全 取代来自神经胶质细胞的营养支持。 另外，我 最近获得了几种针对抗原的单克隆抗体 在损伤诱导期间在特定类别的神经胶质细胞中诱导 海马胆碱能神经支配的萌芽。 本研究的目标是： - 确定哪些分子支持生存和 胆碱能基底前脑神经元的分化。 - 识别产生此类分子的细胞类型。 - 表征特定类别的神经胶质细胞是否表达 表达损伤引起的额外营养支持 抗原。 - 研究损伤引起的分子特性 抗原。 - 研究表达水平和调节 衰老和衰老过程中的营养支持和损伤诱导的抗原 退行性疾病。 使用的方法包括在 在已知神经营养因子和组织存在的情况下进行培养 提取物；基底前脑神经元与不同细胞的共培养 饲养层和饲养层衍生分子的类型；和 生化和免疫化学表征和 相关分子的纯化。