NEUROFIBRILLARY PATHOLOGY IN ALZHEIMER DISEASE

导致神经纤维性疾病发病的细胞事件 阿尔茨海默病(AD)的病理学(NFP)目前知之甚少。这 建议集中在细胞和细胞的致病机制上 亚细胞水平，重点是病变的免疫电子显微镜 在固定良好的脑组织中，通过活组织检查或快速尸检获得。 我们提出了三项研究，它们将为以下方面提供重要的新见解 NFP的发病机制。 第一，营养不良神经突中异常细丝的形态发生 通过对AD的准确定位，研究AD的特点 细胞骨架蛋白在不同类型异常与正常中的表达 细丝。同时，研究将确定是否有 异常细丝和细胞骨架之间的结构连续性。 将使用进一步的形态测量分析来确定组织 正常和异常的细丝以及神经纤维线是否 起源于神经原纤维缠绕的神经元。 第二，我们将确定微管蛋白和 神经丝重亚单位与成对的螺旋丝(PHF)。 浓缩PHF组分中这些蛋白质的鉴定以及 量化将被用来确定两者是否在化学上 完整的PHF组件。在一系列重建实验中，使用 我们将尝试了解神经丝和微管蛋白 基于蛋白质的阿尔茨海默病异常微丝形成的相关因素 互动。 最后，我们将研究衰老或酒精处理的大鼠作为NFP的模型。 在光镜和电子显微镜水平上的免疫细胞化学将 用于描述在大鼠身上看到的变化，并与AD中的NFP进行比较。 这些结果将成为蛋白质化学的前奏。 NFP在大鼠模型中的特征。 这些实验预计将提供关于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 正常和异常结构的相互作用；b)NFH的识别 和微管蛋白作为NFP的组成部分及其在异常中的重要性 以及c)开发了一个研究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.