Localization of fibrillar polymorphs in human brain tissue

人脑组织中纤维状多型体的定位 总结 A β肽和tau蛋白的纤维状聚集体是阿尔茨海默病的定义特征 (AD)但这些结构在疾病病因学中的作用仍然不确定。高 分辨率低温电子显微镜（cryo-EM）和固态NMR（ssNMR）已被用于 产生大量的纤维状多晶型物的分子模型，其中一些或全部可能是相关的 疾病。这些结构模型为研究提供了基础 特定多态性与不同疾病亚型的关联。悬而未决的问题依然存在 关于多晶型物在病例之间和病例内的分布。拟议的工作将适用于，在 原位，一种分辨率高于免疫染色的结构技术;对 淀粉样结构;可以区分纤维状多晶型物;并保持解剖和空间 关系完好无损。初步数据显示，它可以探测完整的缠结和斑块， 未染色的组织。与其他技术一致，这些数据表明， A β结构的多晶型物在盒之间和盒内。类似的协会还没有 证明了tau沉积物，这些关联将在这里进行测试。中央 所提出的工作的假设是，结构多态性的空间分布 将为纤维如何导致疾病提供重要线索。在 在拟议的研究中，将使用脑组织组织切片的X射线显微衍射（XMD） 为了绘制A β和tau的纤维状多晶型物的位置，产生亚细胞（~ 5 μ g/ml）的 毫米级感兴趣区域的多晶型丰度分辨率图。初步工作 （具体目标1）将绘制人类脑组织中A β和tau多态性的分布， 散发性AD病例，包括来自几个脑区的样本。这些结果将被比较 （具体目的2）与（i）MAPT突变病例、（ii）PS1病例和（iii）病例的类似结果 枕叶主导型视觉空间AD与MAPT突变体的比较将证明 具有不同分子形态的tau原纤维是否表现出构象保留 疾病传播期间的特征;与PS1病例比较将提供类似信息 对于A纤维;与枕骨主要视觉空间AD的比较将探测纤维性 构象和多晶型分布的疾病具有明显不同的模式， 进展这些研究的结果将提供一个初步评估， 不同的纤维状多晶型物在疾病进展期间通过朊病毒样过程传播， 提供了对不同菌株与不同菌株相关的机制的见解， 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.