NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE

导致神经系统疾病发病的细胞事件 阿尔茨海默病（AD）中的神经病理学（NFP）知之甚少。 这 该提案的重点是在细胞和 亚细胞水平，重点是病变的免疫电镜 在固定良好的脑组织中，从活检或快速尸检中获得。 我们提出了三项研究，将提供重要的新见解， NFP的发病机制。 首先，在营养不良的神经突中异常细丝的形态发生 AD的特征将通过精确定位来研究， 细胞骨架蛋白在不同类型的异常和正常 细丝。 同时，研究将确定是否存在 异常丝和细胞骨架之间的结构连续性。 进一步的形态学分析将用于确定组织 正常和异常的纤维以及神经纤维是否 起源于带有神经缠结的神经元。 第二，我们将确定微管蛋白和细胞的化学联系。 神经丝重亚基与成对螺旋丝（PHF）。 在富集的PHF级分中鉴定这些蛋白质以及 定量将用于确定两者是否是化学上的 集成PHF组件。 在一系列的重组实验中， 神经丝和微管蛋白，我们将试图了解 基于蛋白质的导致AD中异常丝形成的因素 互动 最后，我们将研究老年或酒精处理的大鼠作为NFP的模型。 将在光镜和电镜水平进行免疫细胞化学检查。 用于表征在大鼠中观察到的变化，并与AD中的NFP进行比较。 这些结果将作为蛋白质化学的前奏 在大鼠模型中的NFP的表征。 预计这些实验将提供以下方面的重要信息： 细胞骨架在NFP形成中的结构作用以及 正常和异常结构相互作用; B）NFH的识别 和微管蛋白作为NFP的成分，以及它们在异常 细丝形成;和c）开发研究NFP的模型。

The cellular events leading to the pathogenesis of neurofibrillary pathology (NFP) in Alzheimer's disease (AD) are poorly understood. This proposal focuses on the pathogenic mechanisms at the cellular and subcellular level and focuses on immunoelectron microscopy of the lesions in well fixed brain tissue, obtained from either biopsy or rapid autopsy. We propose three studies which will provide significant new insights into the pathogenesis of NFP. First, the morphogenesis of abnormal filaments in the dystrophic neurites characteristic of AD will be studied by the accurate localization of cytoskeletal proteins in the different types of abnormal and normal filaments. In conjunction, studies will establish whether there is structural continuity between the abnormal filaments and the cytoskeleton. Further morphometric analysis will be used to determined the organization of the normal and abnormal filaments and whether neuropil threads originate from neurofibrillary tangle bearing neurons. Second, we will determine the chemical association of tubulin and the neurofilament heavy subunit with paired helical filaments (PHF). Identification of these proteins in enriched PHF fractions as well as quantification will be used to establish whether both are chemically integral PHF components. In a series of reconstitution experiments using neurofilament and microtubule proteins we will attempt to understand the factors responsible for abnormal filament formation in AD based on protein interaction. Finally, we will study the aged or alcohol treated rat as a model of NFP. Immunocytochemistry at the light and electron microscopic levels will be used to characterize the changes seen in rats and compared to NFP in AD. These results will serve as the prelude to protein chemical characterization of NFP in the rat model. These experiments are expected to provide significant information on a) the structural role the cytoskeleton plays in NFP formation as well as the interaction of normal and abnormal structures; b) identification of NFH and tubulin as components of NFP as well as their importance in abnormal filament formation; and c) development of a model to study NFP.