Kinetics of tau aggregation reveals patient-specific tau characteristics among Alzheimer's cases.
Kinetics of tau aggregation reveals patient-specific tau characteristics among Alzheimer's cases.
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DOI：
10.1093/braincomms/fcab096
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发表时间：
2021
影响因子：
4.8
通讯作者：
Dujardin S
中科院分区：
文献类型：
--
作者：
Kamath TV;Klickstein N;Commins C;Fernandes AR;Oakley DH;Frosch MP;Hyman BT;Dujardin S
tau聚集体在整个人脑中的积累是许多被分类为tau蛋白病的神经退行性病症的标志。越来越多的证据表明，tau蛋白聚集以“朊病毒样”的方式发生，其中少量错误折叠的tau蛋白可以诱导其他原始tau蛋白聚集。已经发现Tau聚集体在不同的Tau蛋白病中在结构上不同。然而，最近，我们已经提出，tau寡聚体物种可能在散发性阿尔茨海默病患者个体之间存在生物化学差异，并且还表明，使用基于细胞的生物测定法测量的tau物种的生物活性在个体之间也存在差异。在这里，我们采用了活细胞成像的方法，以标准的基于细胞的生物测定，以进一步探讨聚集的动力学是否也区分这些患者。我们发现，聚集可以观察到在所有情况下遵循一致的模式，具有滞后期，生长期和平台期，每个阶段提供定量参数，通过这些参数我们表征聚集动力学。滞后期的长度和平台期的大小都取决于有接种能力的tau蛋白的浓度，其相对富集在患者之间不同。生长期的斜率与tau聚集体的形态差异相关，这可能反映了潜在的结构差异。这种动力学测定证实并完善了阿尔茨海默病个体中tau蛋白种子特征异质性的概念，并且是未来研究可以表征tau聚集和可能影响这些变化的细胞过程的纵向变化的方法。在报告基因测定中，Kamath等人报道了来自散发性阿尔茨海默病患者的脑样品中tau聚集在个体间的动力学差异，反映了初始种子的性质，并表明即使在散发性阿尔茨海默病个体中tau病理生物学的个体特异性差异。
The accumulation of tau aggregates throughout the human brain is the hallmark of a number of neurodegenerative conditions classified as tauopathies. Increasing evidence shows that tau aggregation occurs in a ‘prion-like’ manner, in which a small amount of misfolded tau protein can induce other, naïve tau proteins to aggregate. Tau aggregates have been found to differ structurally among different tauopathies. Recently, however, we have suggested that tau oligomeric species may differ biochemically among individual patients with sporadic Alzheimer disease, and have also showed that the bioactivity of the tau species, measured using a cell-based bioassay, also varied among individuals. Here, we adopted a live-cell imaging approach to the standard cell-based bioassay to explore further whether the kinetics of aggregation also differentiated these patients. We found that aggregation can be observed to follow a consistent pattern in all cases, with a lag phase, a growth phase and a plateau phase, which each provide quantitative parameters by which we characterize the aggregation kinetics. The length of the lag phase and magnitude of the plateau phase are both dependent upon the concentration of seeding-competent tau, the relative enrichment of which differs among patients. The slope of the growth phase correlates with morphological differences in the tau aggregates, which may be reflective of underlying structural differences. This kinetic assay confirms and refines the concept of heterogeneity in the characteristics of tau proteopathic seeds among individuals with Alzheimer’s disease and is a method by which future studies may characterize longitudinal changes in tau aggregation and the cellular processes which may influence these changes. In a reporter assay, Kamath et al. report differences in the kinetics of tau aggregation accross individuals in brain samples from sporadic Alzheimer patients reflecting the properties of the initial seeds and suggesting person-specific differences in tau pathobiology even among individuals with sporadic Alzheimer disease.