Localization of fibrillar polymorphs in human brain tissue

纤维多态基因在人脑组织中的定位 摘要 多肽和tau蛋白的纤维聚集是阿尔茨海默病的特征 (AD)但这些结构在疾病病因学中所起的作用仍不确定。高 分辨率低温电子显微镜(CRYO-EM)和固体核磁共振(SS核磁共振)已被用于 生成一系列纤维多态的分子模型，其中一些或全部可能是相关的 为了疾病。这些结构模型为研究演示 特定多态与不同疾病亚型的关联。悬而未决的问题仍然存在 关于多态在病例之间和病例内的分布。拟议的工作将适用于 原位技术，一种分辨率高于免疫染色的结构技术；对 淀粉样蛋白结构；可以区分纤维多形性；并保持解剖和空间 关系完好无损。初步数据显示，它可以完整地探测到缠结和斑块 未染色的组织。与其他技术一致，这些数据表明有 病例间和病例内结构的多态。类似的联想还有待于 演示了Tau矿藏，这些关联将在这里进行测试。中环 拟议工作的假设是结构多态的空间分布 将提供有关纤维如何导致疾病的重要线索。在 拟议的研究，将使用脑组织组织切片的X射线微衍射(XMD) 为了定位A和tau的纤维多态的位置，产生亚细胞(~5 毫米级感兴趣区域内多态丰度的分辨率贴图。初始工作 (特定目标1)将绘制A和tau多态在人脑组织中的分布 散发性阿尔茨海默病病例，包括来自几个大脑区域的样本。这些结果将被比较 (具体目标2)与(I)MAPT突变病例、(Ii)PS1病例和(Iii)病例的类似结果 枕部占优势的视觉空间AD。与MAPT突变体的比较将证明 具有不同分子形态的tau纤维是否表现出构象保留 疾病传播过程中的特征；与PS1病例进行比较将提供类似的信息 对于纤维；与枕骨优势视觉空间AD的比较将探测纤维 具有明显不同模式的疾病的构象和多态分布 进步。这些研究的结果将提供对是否 在疾病进展和发展过程中，不同的纤维多形性通过类似病毒的过程传播 深入了解不同菌株与不同菌株之间的关联机制 疾病亚型。

Localization of fibrillar polymorphs in human brain tissue Summary Fibrillar aggregates of A peptides and tau protein are defining features of Alzheimer's disease (AD) but the role these structures play in the etiology of disease remains uncertain. High resolution cryo-electron microscopy (cryo-EM) and solid-state NMR (ssNMR) have been used to generate a host of molecular models of fibrillar polymorphs, some or all of which may be relevant to disease. These structural models have provided the foundation for studies demonstrating an association of specific polymorphs with different disease subtypes. Outstanding questions remain as to the distribution of polymorphs between and within cases. The proposed work will apply, in situ, a structural technique that has resolution higher than immunostaining; is very sensitive to amyloid structure; can distinguish between fibrillar polymorphs; and keeps anatomical and spatial relationships intact. Preliminary data show that it can probe both tangles and plaques in intact unstained tissue. In agreement with other techniques, these data indicate that there are polymorphs of A structure between and within cases. Analogous associations have yet to be demonstrated for tau deposits, and those associations will be tested here. The central hypothesis of the proposed work is that the spatial distribution of structural polymorphs in brain tissue will provide important clues as to how fibrils contribute to disease. In the proposed studies, X-ray microdiffraction (XMD) of histological sections of brain tissue will be used to map the locations of fibrillar polymorphs of both A and tau, generating sub-cellular (~ 5  resolution maps of polymorph abundances across millimeter-scale regions of interest. Initial work (Specific Aim 1) will map the distribution of A and tau polymorphs in human brain tissue in sporadic AD cases, including samples from several brain regions. These results will be compared (Specific Aim 2) to analogous results from (i) MAPT mutant cases, (ii) PS1 cases and to (iii) cases of occipital predominant visuo-spatial AD. Comparison to MAPT mutants will demonstrate whether tau fibrils with distinct molecular morphologies exhibit preservation of conformational signatures during disease spread; comparison with PS1 cases will provide analogous information for A fibrils; comparison with occipital predominant visuo-spatial AD will probe fibrillar conformations and polymorph distributions in disease with distinctly different patterns of progression. The results of these studies will provide a preliminary assessment of whether or not different fibrillar polymorphs spread by a prion-like process during disease progression and provide insights into the mechanisms by which different strains are associated with different disease subtypes.