Kamath Tarun V, Klickstein Naomi, Commins Caitlin, Fernandes Analiese R, Oakley Derek H, Frosch Matthew P, Hyman Bradley T, Dujardin Simon
Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Harvard Medical School, Boston, MA 02115, USA.
Brain Commun. 2021 May 4;3(2):fcab096. doi: 10.1093/braincomms/fcab096. eCollection 2021.
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.
tau蛋白聚集体在整个人脑中的积累是多种被归类为tau蛋白病的神经退行性疾病的标志。越来越多的证据表明，tau蛋白聚集以“朊病毒样”方式发生，即少量错误折叠的tau蛋白可诱导其他未折叠的tau蛋白聚集。已发现tau蛋白聚集体在不同的tau蛋白病中结构不同。然而，最近我们提出，tau蛋白寡聚体在散发性阿尔茨海默病个体患者中可能存在生化差异，并且还表明，使用基于细胞的生物测定法测量的tau蛋白种类的生物活性在个体之间也有所不同。在这里，我们采用活细胞成像方法对基于细胞的标准生物测定进行研究，以进一步探索聚集动力学是否也能区分这些患者。我们发现，在所有情况下都能观察到聚集遵循一致的模式，包括延迟期、生长期和平稳期，每个阶段都提供了定量参数，据此我们可以描述聚集动力学。延迟期的长度和平稳期的幅度均取决于具有播种能力的tau蛋白的浓度，而其相对丰度在患者之间有所不同。生长期的斜率与tau蛋白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患者个体中tau蛋白病种子特征异质性的概念，并且是一种未来研究可用于描述tau蛋白聚集的纵向变化以及可能影响这些变化的细胞过程的方法。
