NERVE GROWTH FACTOR IN ALZHEIMER'S DISEASE

阿尔茨海默病的病因尚不清楚。然而，最近 结果有力地支持了淀粉样蛋白改变的假设 加工可能是这种疾病的主要神经病理特征的基础。 疾病(老年斑和神经原纤维缠结)。此外, 相当多的证据支持这样的结论，即基底前脑 胆碱能神经元也在这种疾病中受到影响，可能与 到助记症状学。一种假设是， 基底前脑神经元反映营养关系的中断 大脑皮层和皮质下的目标。尤其是， 证明神经生长因子(NGF)存在于中枢神经系统，如 以及其对基底前脑的药理作用 啮齿动物和灵长类动物中的胆碱能神经元导致了这一假说 神经生长因子的减少是基底前脑退变的基础 阿尔茨海默病中的神经元和NGF可能是有用的 从治疗上讲。此外，经典的演示， 老年斑块区域的“营养不良”神经突起被认为是 反映营养活动异常(或增加或减少) 这些区域。这个实验室的最新结果表明， 在阿尔茨海默病皮质的NGF样免疫反应中。此外，组织 用阿尔茨海默病脑组织切片进行的培养实验 证明老年斑改变了培养中神经元的形态并出现 抑制神经突起的生长。根据这些初步调查结果， 本申请中概述的工作将集中在两个主要假设上： 1)阿尔茨海默病的特征是神经生长因子增加，这是由于 基底前脑退行性改变和2)老年斑 对培养中轴突生长的抑制作用。这些假设 将通过测量NGF样免疫反应性进行实验测试 几种皮质中敏感的双部位免疫学和生物学检测 以及阿尔茨海默氏症和对照组大脑的皮质下区域。在……里面 为了确定斑块对轴突生长的影响， 鸡交感神经细胞的分离和组织块培养 建立在阿尔茨海默氏症和对照组大脑的组织切片上。这个 生长锥与衰老斑块的动态相互作用将是 通过对培养中的活神经元进行活性染色进行监测。整体而言 拟议工作的目标是确定NGF可能具有的作用(如果有的话) 阿尔茨海默病以及老年斑是否代表 对活神经元的负面影响。这些问题的答案将 允许评估在此治疗中使用NGF的理论基础 疾病，以及解决目前关于 老年斑在阿尔茨海默病的病因中起作用。

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.