NERVE GROWTH FACTOR IN ALZHEIMER'S DISEASE

阿尔茨海默病的病因仍然未知。 但最近的 结果强烈支持淀粉样蛋白的改变 处理可能是这种疾病的主要神经病理学特征的基础。 疾病（老年斑和神经纤维缠结）。 此外，本发明还提供了一种方法， 大量证据支持基底前脑 胆碱能神经元也在这种疾病中受到影响， 到记忆学 一种假设是， 基底前脑神经元反映了营养关系的破坏 大脑皮层和皮层下的目标 特别是 证明神经生长因子（NGF）存在于CNS中， 以及其对基底前脑的明显药理作用 啮齿动物和灵长类动物的胆碱能神经元，导致了一种假设， 神经生长因子的减少是基底前脑退化的基础 神经元在阿尔茨海默病和神经生长因子可能是有用的 治疗上 此外，经典的示范， 老年斑区域的“营养不良”神经突被认为 反映异常（增加或减少）的营养活性， 这些地区 该实验室的最新结果表明， 神经生长因子样免疫反应性。 此外，组织 用阿尔茨海默氏症的脑组织切片进行的培养实验 表明老年斑改变了培养物中的神经元形式， 抑制神经突生长 在这些初步调查结果的基础上， 本申请中概述的工作将集中于两个主要假设： 1)阿尔茨海默氏病的特征是由于神经生长因子的增加， 基底前脑的退行性变化和2）老年斑块表现出 对培养物中神经突生长的抑制作用。 这些假设 将通过测量NGF样免疫反应性进行实验测试， 在几种皮质中进行灵敏的2位点免疫学和生物学测定 和大脑皮层下的区域。 在 为了确定斑块对神经突生长的影响， 将分离和移植培养的鸡交感神经元， 建立在阿尔茨海默氏症和对照组大脑的组织切片上。 的 生长锥与老年斑的动态相互作用将是 使用培养物中活神经元的活体染色进行监测。 整体 这项工作的目标是确定神经生长因子可能发挥的作用（如果有的话 以及老年斑是否代表 对活体神经元的负面影响。 这些问题的答案将 允许评估使用神经生长因子治疗的基本原理， 疾病以及解决目前的争议的作用， 老年斑在阿尔茨海默病的病因学中起作用。

The etiology of Alzheimer's disease remains unknown. However, recent results strongly support the hypothesis that alterations in amyloid processing may underlie the chief neuropathological features of this disorder (senile plaques and neurofibrillary tangles). In addition, considerable evidence supports the conclusion that the basal forebrain cholinergic neurons are also affected in this disease and may contribute to the mnemonic symptomatology. One hypothesis is that alterations in basal forebrain neurons reflect a disruption of trophic relationships with their cortical and subcortical targets. In particular, the demonstration that Nerve Growth Factor (NGF) is present in the CNS, as well as its demonstrable pharmacological effects on basal forebrain cholinergic neurons in rodents and primates, have led to the hypothesis that reductions in NGF underlie the degeneration of basal forebrain neurons in Alzheimer's disease and that NGF might be useful therapeutically. furthermore, the classical demonstration of "dystrophic" neurites in regions of senile plaques has been suggested to reflect abnormal (either increased or decreased) trophic activity in these areas. Recent results from this laboratory demonstrate an increase in NGF-like immunoreactivity in Alzheimer's cortex. In addition, tissue culture experiments carried out with sections of Alzheimer's brain tissue demonstrate that senile plaques alter neuronal form in culture and appear to inhibit neurite outgrowth. Building on these initial findings, the work outlined in this application will focus on two major hypotheses: 1) Alzheimer's disease is characterized by an increase in NGF due to degenerative changes in the basal forebrain and 2) Senile plaques exhibit inhibitory effects on neurite outgrowth in culture. These hypotheses will be tested experimentally by measuring NGF-like immunoreactivity with sensitive 2-site immunological and biological assays in several cortical and subcortical brain regions from Alzheimer's and control brains. In order to determine the effect that plaques have on neurite outgrowth, dissociated and explant cultures of chick sympathetic neurons will be established on tissue sections from Alzheimer's and control brains. The dynamic interactions of growth cones with senile plaques will be monitored using vital staining of living neurons in culture. The overall goal of the proposed work is to determine what role, if any, NGF may have in Alzheimer's disease and whether senile plaques represent sites of negative influence on living neurons. Answers to these questions will permit assessment of the rationale for using NGF therapeutically in this disease as well as address the current controversy over the role that senile plaques play in the etiology of Alzheimer's disease.