Fibrillar polymorphs in human brain tissue

人脑组织中的纤维蛋白多态 项目摘要 阿尔茨海默病(AD)是一种神经退行性疾病，定义为β蛋白沉积 多肽和tau蛋白。阿尔茨海默病的进展涉及tau沉积，称为神经纤维缠结，沿着 大脑中的解剖路径被绘制得很好。皮克氏病、额颞叶痴呆症、 进行性核上性麻痹(和其他)在整个脑部都与不同的病理模式有关。 脑部与临床表型的相应差异。Tau的纤维多晶型结构有 在高分辨率下被测定，并且在主要的异构体/多晶型上存在公认的差异 与每一种疾病相关的tau蛋白。有人提出，在组成、结构上的差异 和tau寡聚体/原纤维的翻译后修饰(PTM)导致个体之间的差异 影响疾病属性的生物活性，如发病年龄、进展率和解剖分布 病理学。为了验证这一假设，我们将使用多种方法在不同的脑区对tau进行原位观察。 在疾病的不同阶段。这个项目的一个中心假设是，询问tau的结构 疾病进展过程中完整组织中的聚集体可以阐明同质性或异质性 是导致个人阿尔茨海默病表型的tau沉积的主要特征。进阶 将使用技术来制备人脑样本，并使扫描x射线微衍射(XMD)能够 在分子水平上原位绘制结构变异的分布图。标测纤维和纤维的分布 Tau病变内部和之间的非纤维结构将提供疾病程度的衡量标准 进化是由类Pron扩散驱动的，并阐明了非纤维凝聚体在种子和原纤维中的作用 成核作用。病变结构组织的演变将通过对不同区域的研究来跟踪 Braak第二阶段以后的大脑。对于每个病例，独立于疾病阶段，整个tau-Braak通路将 被调查以检测任何可能先于或同时发生的组织结构前纤维沉积或改变 伴随着纤维病理的出现。对典型AD病例的观察结果将与类似病例进行比较 Pick病、进行性核上性麻痹(PSP)、额颞叶变性(FTLD-Tau)的研究 带有P301L tau突变的tau病理)和弹性病例(其中观察到高斑块负荷在 没有明显的临床痴呆)。这将定义纤维结构和组织的变化范围 并测试疾病特异性多态与脑组织相互作用的假设 不同的方式导致不同的病理解剖分布和疾病表型的变异。 跨大脑区域和疾病不同阶段的观察结果的关联将使检测成为可能 斑块和缠结的分子结构的模式，构建一系列可能 揭示因果关系并阐明潜在分子过程的性质，以此作为识别 分子间的相互作用对疾病的发展至关重要，因此容易受到临床干预。

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.