Fibrillar polymorphs in human brain tissue

人脑组织中的纤维多态性

• 批准号: 10733496
• 负责人: LEE MAKOWSKI
• 金额: $ 211.23万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733496
• 关键词: Age of Onset; Alzheimer' s Disease; Amyloid beta-Protein; Anatomy; Appearance; Area; Binding; Brain; Brain Injuries; Brain region; Characteristics; Clinical; Cryoelectron Microscopy; Data; Data Set; Dementia; Deposition; Detection; Development; Disease; Disease Progression; Event; Evolution; Fostering; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Generations; Growth; Heterogeneity; Human; Immunohistochemistry; In Situ; Individual; Intervention; Knowledge; Lead; Length; Lesion; Link; Location; Maps; Measures; Metadata; Methods; Molecular; Molecular Structure; Mutation; Nature; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropathy; Pathologic; Pathology; Pathway interactions; Pattern; Peptides; Phase; Phenotype; Physical condensation; Pick Disease of the Brain; Polymorph; Predisposition; Process; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; Resolution; Roentgen Rays; Role; Sampling; Scanning; Shapes; Structure; Symptoms; Tauopathies; Techniques; Testing; Tissues; Variant; Work; abeta accumulation; biophysical tools; brain tissue; cerebral atrophy; clinical phenotype; disease heterogeneity; disease phenotype; disorder subtype; falls; insight; migration; multidisciplinary; nanoscale; neural; preservation; prion-like; protein aggregation; resilience; searchable database; tau Proteins; tau aggregation; tau mutation; tau-1

Fibrillar polymorphs in human brain tissue Project Summary Alzheimer's disease (AD) is a neurodegenerative disorder defined by the accumulation of protein deposits of Aβ peptide and tau protein. Progression of AD involves spread of tau deposits, called neurofibrillary tangles, along well charted anatomical pathways in the brain. Tauopathies such as Pick’s disease, frontotemporal dementia, progressive supranuclear palsy (and others) are associated with alternate patterns of pathology throughout the brain with the consequent differences in clinical phenotypes. The structures of fibrillar polymorphs of tau have been determined at high resolution and there are well-established differences in the dominant isoform/polymorph of tau associated with each of these diseases. It has been suggested that differences in composition, structure and post-translational modifications (PTMs) of tau oligomers/fibrils among individuals lead to differences in bioactivity that impact disease attributes such as age of onset, rate of progression and anatomical distribution of pathology. In order to test that hypothesis, methods will be used to observe tau in situ, in different brain areas and at different phases of disease. A central hypothesis of this project is that interrogating the structure of tau aggregates in the context of intact tissue during disease progression can clarify if homogeneity or heterogeneity is the predominant feature of tau deposits that contribute to an individual’s Alzheimer phenotype. Advanced techniques will be used to prepare human brain samples and enable scanning x-ray microdiffraction (XMD) to map in situ the distribution of structural variations at the molecular level. Mapping the distribution of fibrillar and non-fibrillar structure within and among tau lesions will provide a measure of the degree to which disease progression is driven by prion-like spreading and clarify the role of non-fibrillar condensates in seed and fibril nucleation. Evolution of the structural organization of lesions will be tracked by studies of different regions of the brain at Braak stage II onward. For each case, independent of disease stage, the entire tau-Braak pathway will be investigated to detect any pre-fibrillar deposits or alterations in tissue structure that may precede or coincide with the emergence of fibrillar pathology. Observations in typical AD cases will be compared with analogous studies of Pick's disease, progressive supranuclear palsy (PSP), FTLD-Tau (Frontotemporal lobar degeneration with tau pathology with P301L tau mutations) and resilient cases (in which high plaque burden is observed in the absence of overt clinical dementia). This will define the breadth of variation in fibrillar structure and organization in these neuropathies and test the hypothesis that disease-specific polymorphs interact with brain tissue in distinct ways that lead to different anatomical distributions of pathology and variation in disease phenotype. Correlation of observations across brain regions and at various stages of disease will make possible detection of patterns in the molecular structure of plaques and tangles, construction of a sequence of events that may reveal causal relationships and clarify the nature of underlying molecular processes as a basis for identifying molecular interactions essential to disease progression and thereby susceptible to clinical intervention.

人脑组织中的纤维状多型体 项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以Aβ蛋白沉积为特征的神经退行性疾病 肽和tau蛋白。AD的进展涉及tau沉积物的扩散，称为神经元缠结，沿着 大脑中清晰的解剖路径Tauopathies如Pick's病，额颞叶痴呆， 进行性核上性麻痹（和其他）与整个病程中的交替病理模式有关。 大脑中的临床表型的差异。tau蛋白的纤维状多晶型物的结构具有 在高分辨率下测定，并且在主要亚型/多晶型中存在明确的差异 与这些疾病相关的tau蛋白。有人认为，成分、结构 个体之间tau寡聚体/原纤维的翻译后修饰（PTM）导致以下差异： 生物活性影响疾病属性，如发病年龄、进展速度和解剖分布， 病理为了验证这一假设，将使用各种方法在不同的大脑区域原位观察tau蛋白 在疾病的不同阶段。该项目的一个中心假设是探究tau的结构 疾病进展期间完整组织中的聚集物可以澄清同质性或异质性 是导致个体阿尔茨海默病表型的tau沉积的主要特征。先进 技术将用于制备人脑样本，并使扫描X射线显微衍射（XMD）， 在分子水平上原位绘制结构变异的分布图。绘制纤维状和 tau病变内和之间的非纤维状结构将提供疾病 进展是由朊病毒样扩散驱动的，并阐明了种子和原纤维中非纤维状凝聚物的作用。 成核病变的结构组织的演变将通过对不同区域的研究来跟踪。 大脑处于Braak II期对于每个病例，无论疾病阶段如何，整个tau-Braak途径都将 进行研究，以检测可能先于或同时发生的组织结构中的任何前纤维沉积或改变 随着纤维病理学的出现。典型AD病例的观察结果将与类似的 皮克病、进行性核上性麻痹（PSP）、FTLD-Tau（额颞叶变性） 具有P301 L tau突变的tau病理学）和弹性病例（其中在P301 L tau突变中观察到高斑块负荷）。 没有明显的临床痴呆）。这将确定纤维结构和组织的变化幅度 在这些神经病变和测试的假设，疾病特异性多态性与脑组织相互作用， 不同的方式导致病理学的不同解剖分布和疾病表型的变化。 将不同脑区和疾病不同阶段的观察结果相关联， 斑块和缠结的分子结构模式，一系列事件的构建， 揭示因果关系，并澄清潜在的分子过程的性质，作为识别 分子相互作用对疾病进展至关重要，从而易于临床干预。