Localization of fibrillar polymorphs in human brain tissue

人脑组织中纤维状多晶型物的定位

• 批准号: 10043200
• 负责人: LEE MAKOWSKI
• 金额: $ 43.18万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043200
• 关键词: Address; Agreement; Alzheimer' s Disease; Amyloid; Anatomy; Area; Brain; Brain region; Cryoelectron Microscopy; Data; Deposition; Disease; Disease Progression; Etiology; Exhibits; Foundations; Goals; Heart; Histologic; Human; In Situ; Length; Ligand Binding; Location; Maps; Molecular; Molecular Conformation; Morphology; Neurofibrillary Tangles; Pathologic; Pattern; Peptides; Play; Polymorph; Positron-Emission Tomography; Process; Resolution; Roentgen Rays; Role; Sampling; Spatial Distribution; Structural Models; Structure; Techniques; Testing; Tissues; Variant; Visuospatial; Work; amyloid structure; brain tissue; disease phenotype; disorder subtype; insight; interest; millimeter; molecular modeling; mutant; preservation; prion-like; protein aggregation; solid state nuclear magnetic resonance; spatial relationship; tau Proteins; tau conformation

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.

人脑组织中纤维状多晶型物的定位 概括 A 肽和 tau 蛋白的纤维状聚集体是阿尔茨海默氏病的定义特征 (AD) 但这些结构在疾病病因学中所起的作用仍不确定。 分辨率冷冻电子显微镜（cryo-EM）和固态核磁共振（ssNMR）已被用于 生成大量纤维状多晶型物的分子模型，其中一些或全部可能相关 这些结构模型为证明疾病的研究提供了基础。 特定多晶型物与不同疾病亚型的关联仍然是悬而未决的问题。 关于病例之间和病例内多晶型物的分布，拟议的工作将适用于。 原位结构技术比免疫染色具有更高的分辨率，对以下情况非常敏感； 淀粉样蛋白结构；可以区分纤维状多晶型物并保持解剖学和空间性； 初步数据关系表明，它可以探测完整的缠结和斑块。 与其他技术一致，这些数据表明存在。 病例之间和病例内的 A 结构的多态性尚未建立。 演示了 tau 存款，这些关联将在这里进行测试。 所提出的工作的假设是结构多晶型物的空间分布 脑组织中的纤维将为了解原纤维如何导致疾病提供重要线索。 拟议的研究中，将使用脑组织组织切片的 X 射线微衍射 (XMD) 绘制 A 和 tau 纤维状多晶型物的位置，生成亚细胞 (~ 5  毫米级感兴趣区域的多晶型丰度的分辨率图。 （具体目标 1）将绘制 A 和 tau 多态性在人脑组织中的分布图 零星的 AD 病例，包括来自几个大脑区域的样本，这些结果将被进行比较。 （具体目标 2）来自 (i) MAPT 突变病例、(ii) PS1 病例和 (iii) 病例的类似结果 与 MAPT 突变体的比较将证明枕叶主导的视觉空间 AD。 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 病例的比较将提供类似信息 对于 A 原纤维；与枕叶主导的视觉空间 AD 进行比较将探测原纤维 疾病中的构象和多晶型分布具有明显不同的模式 这些研究的结果将提供一个初步评估： 在疾病进展过程中，不同的纤维状多晶型物通过类似朊病毒的过程传播， 提供对不同菌株与不同菌株相关的机制的见解 疾病亚型。