Fibrillar polymorphs in human brain tissue

人脑组织中的纤维多态性 项目概要 阿尔茨海默病 (AD) 是一种神经退行性疾病，其特征是 Aβ 蛋白沉积物的积累 肽和 tau 蛋白。 AD 的进展涉及 tau 沉积物（称为神经原纤维缠结）的扩散， 大脑中清晰的解剖路径。 tau蛋白病，例如皮克氏病、额颞叶痴呆、 进行性核上性麻痹（和其他）与整个身体的不同病理模式有关 大脑与随之而来的临床表型差异。 tau 纤维状多晶型物的结构 已在高分辨率下确定，并且主要亚型/多晶型物存在明确的差异 与这些疾病相关的 tau 蛋白。有人认为，成分、结构上的差异 个体之间 tau 寡聚体/原纤维的翻译后修饰 (PTM) 会导致差异 影响疾病属性的生物活性，例如发病年龄、进展速度和解剖学分布 病理学。为了验证这一假设，我们将使用方法在不同的大脑区域原位观察 tau 蛋白 以及疾病的不同阶段。该项目的一个中心假设是探究 tau 蛋白的结构 在疾病进展过程中在完整组织的背景下聚集可以澄清同质性还是异质性 是导致个体阿尔茨海默病表型的 tau 蛋白沉积物的主要特征。高级 技术将用于制备人脑样本，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。绘制原纤维的分布图 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 进展是由朊病毒样扩散驱动的，并阐明了非原纤维凝聚物在种子和原纤维中的作用 成核。将通过对不同区域的研究来跟踪病变结构组织的演变 大脑处于 Braak II 期以后。对于每个病例，无论疾病阶段如何，整个 tau-Braak 通路都会 进行研究以检测可能先于或同时发生的任何前原纤维沉积或组织结构的改变 随着纤维病理学的出现。典型 AD 病例的观察结果将与类似病例进行比较 皮克氏病、进行性核上性麻痹 (PSP)、FTLD-Tau（额颞叶变性）的研究 具有 P301L tau 突变的 tau 病理学病例）和恢复性病例（其中在 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 在这些神经病中，并检验疾病特异性多晶型物与脑组织相互作用的假设 导致病理学不同解剖分布和疾病表型变异的不同方式。 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模式，构建可能的一系列事件 揭示因果关系并阐明潜在分子过程的本质，作为识别的基础 分子相互作用对于疾病进展至关重要，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.