ABNORMAL FIBROUS ASSEMBLIES OF ALZHEIMER'S DISEASE

成对螺旋丝的分子结构，淀粉样斑块 核心，和脑血管淀粉样蛋白分离自阿尔茨海默病（AD） 大脑将使用X射线衍射和电子显微镜进行研究。 高分辨率X射线图案将从分离的 用于与体外模式比较的异常纤维集合体 与AD具有序列同源性的合成多肽的组装体 淀粉样β蛋白 为了获得适合于这种比较的模式， 将通过将颗粒或浓缩溶液暴露于 2特斯拉的外部磁场。 磁致取向 类似的丝状结构（如丝状噬菌体一样多样， 整个视网膜杆，核酸和镰状细胞血红蛋白纤维）， 以前已经证明，大大提高质量的 衍射数据 我们的各种纤维集合体的X射线散射 也将通过改变浴槽的电子密度来增强 培养基，使用阴性染色剂，并标记反应性氨基酸残基 重金属。 适当对比和良好定向的颗粒将 允许检测由填充产生的弱散射 纤维内和沿着纤维的结构单元。 准确测定 X射线反射的间隔和积分宽度将 提供衍射区域的尺寸和长度的测量 组成结构的多肽链。 确定结构单元的尺寸和空间组织 包括成对的螺旋丝、AD淀粉样蛋白和体外组装 将阐明我们对它们的形成，相互关系， 而他们，又是怎样的一个人。 来源于神经元中正常存在的细胞骨架成分。 的 更普遍的兴趣，我们的研究结果也将是相关的系统 淀粉样变性和蛋白质折叠的问题。

The molecular organization of paired helical filaments, amyloid plaque cores, and cerebrovascular amyloid isolated from Alzheimer's disease (AD) brain will be studied using X-ray diffraction and electron microscopy. High-resolution X=ray patterns will be obtained from isolates of the abnormal fibrous assemblies for comparison with patterns from in vitro assemblies of synthetic polypeptides having sequence homologies with the AD amyloid beta-protein. To obtain patterns that are suitable for such comparisons, the assemblies will be oriented by exposure of pellets or concentrated solutions to an external magnetic field of 2 Tesla. The magnetically-induced orientation of similar filamentous structures (as diverse as filamentous bacteriophage, whole retinal rods, nucleic acids, and sickle cell hemoglobin fibers) has been previously shown to substantially enhance the quality of the diffraction data. The X-ray scatter from our various fibrous assemblies will also be enhanced by altering the electron density of the bathing medium, using negative stains, and labeling reactive amino acid residues with heavy metals. Appropriately contrasted and well-oriented pellets will allow the detection of weak scatter that arises from the packing of the structural units within and along the fibres. Accurate determination of the spacings and of the integral widths of the X-ray reflections will provide a measure of the sizes of the diffracting regions and the lengths of the polypeptide chains constituting the structure. Determining the dimensions and spatial organization of the structural units that comprise paired helical filaments, AD amyloids and in vitro assemblies will illuminate our understanding of their formation, interrelationships, and stability, and will provide insight on how they might be related to or derive from normally occurring cytoskeletal components in the neuron. Of more general interest, our findings will also be relevant to the systemic amyloidoses, and to the problem of protein folding.