NEUROTROPHIC SUPPORT IN AGING & ALZHEIMER'S DISEASE

企业发展和维护的调控机制 复杂而特殊的神经支配模式是 哺乳动物的中枢神经系统仍然知之甚少。 然而，几个独立的观察表明，有两个 不同类型的特定细胞外分子信号发挥着 在这一过程中发挥重要作用。第一类信号是可溶信号 支持生存和分化的神经营养因子 特定类型的神经元，第二种信号类型是 被认为是由不溶分子组成的，这些分子提供了 选择性黏附于生长中的轴突。身份识别和 这种分子信号的特征，以及知道 这些分子的表达是如何调控的，是关键 对了解神经支配模式如何发展很重要 并得到维护。我们特别感兴趣的是确定 这类分子在衰老过程中并调查是否存在干扰 其作用与神经退行性变的病因学有关 疾病，如阿尔茨海默病(AD)。 这项提案描述了一项研究，重点是确定 提供营养信号的细胞类型和分子 支配海马区的基底前脑胆碱能神经元 和大脑皮层。它还将研究如何表达 神经营养支持受到调节，这种作用是什么 在老龄化和AD方面提供支持。此前，在与其他人的合作下， 我已经证明神经生长因子(NGF)促进 胆碱能基底前脑神经元的分化。 初步结果表明，仅有NGF不能完全 替代来源于神经胶质细胞的营养支持。此外，我 最近获得了几种针对抗原的单抗 在损伤诱导过程中在特定类别的神经胶质细胞中诱导 海马胆碱能神经发芽。 这项研究的目标是： -确定哪些分子支持生存和 胆碱能基底前脑神经元的分化。 -识别产生这种分子的细胞类型。 -确定特定类别的神经胶质细胞是否表达 表达损伤诱导的额外营养支持 抗原。 -研究损伤诱导的分子特性 抗原。 -研究基因的表达水平和调控 营养支持和损伤诱导的抗原在衰老和衰老中的作用 退行性疾病。 使用的方法包括在大脑中培养基底前脑神经元 在已知神经营养因子和组织存在下进行培养 提取液与不同来源的基底前脑神经元共培养 饲料层和饲料层衍生分子的类型；以及 生化和免疫化学特征和 相关分子的提纯。

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.