NEUROTROPHIC SUPPORT IN AGING & ALZHEIMER'S DISEASE

神经营养支持衰老

• 批准号: 3453171
• 负责人: FELIX P ECKENSTEIN
• 金额: $ 9.81万
• 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 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3453171
• 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.

调节发展和维护的机制 复杂而特定的神经支配模式的特征 哺乳动物中枢神经系统的理解仍然很差。 但是，七次独立观察表明两个 不同类型的特定细胞外分子信号播放 在此过程中的主要作用。 第一种信号是可溶的 支持生存和分化的神经营养因素 特定类型的神经元，第二种信号为 被认为是由不溶性分子组成的 对生长神经突的选择性粘附。 识别和 这种分子信号的表征以及知道 这些分子的表达如何调节，是中央的 对于理解神经支配模式的发展很重要 并维护。 确定的作用是特别兴趣 这种分子在衰老中，并研究是否干扰 其作用涉及神经退行性的病因 疾病，例如阿尔茨海默氏病（AD）。 该提案描述了一项有关识别的研究 细胞类型和分子为营养信号提供 基础前脑中的胆碱能神经元支配海马 和大脑皮层。 还将研究它的表达方式 神经营养支持受到调节以及这种作用 支持衰老和广告。 以前，与他人合作 我已经表明，神经生长因子（NGF）促进 胆碱能基础前脑神经元的分化。 初步结果表明，仅NGF不能完全 替换从神经胶质细胞中得出的营养支持。 另外，我 最近获得了几种对抗原的单克隆抗体 损伤诱导的特定类别细胞的特定类别诱导 海马胆碱能神经神经的发芽。 这项研究的目标是： - 确定哪些分子支持生存和 胆碱能基础前脑神经元的分化。 - 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。 - 研究损伤诱导的分子特性 抗原。 - 研究表达的水平和调节 营养支撑和损伤诱导的抗原在衰老和 退化性疾病。 要使用的方法包括生长基础前脑神经元 在存在已知神经营养因子和组织的存在下培养 提取物；基础前脑神经元共培养不同 进料器层和进料器衍生的分子的类型；和 生化和免疫化学特征和 相关分子的纯化。