Manos Justine D, Preiss Christina N, Venkat Nandini, Tamm Joseph, Reinhardt Peter, Kwon Taekyung, Wu Jessica, Winter Allison D, Jahn Thomas R, Yanamandra Kiran, Titterton Katherine, Karran Eric, Langlois Xavier
Abbvie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA 02139, USA.
AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
iScience. 2021 Dec 18;25(1):103658. doi: 10.1016/j.isci.2021.103658. eCollection 2022 Jan 21.
Tau pathobiology has emerged as a key component underlying Alzheimer's disease (AD) progression; however, human neuronal models have struggled to recapitulate tau phenomena observed . Here, we aimed to define the minimal requirements to achieve endogenous tau aggregation in functional neurons utilizing human induced pluripotent stem cell (hiPSC) technology. Optimized hiPSC-derived cortical neurons seeded with AD brain-derived competent tau species or recombinant tau fibrils displayed increases in insoluble, endogenous tau aggregates. Importantly, wild type and mutant hiPSC-neurons exhibited unique propensities for aggregation dependent on the seed strain rather than the repeat domain identity, suggesting that successful templating of the recipient tau may be driven by the unique conformation of the seed. The model presented here represents the first successful demonstration of combining human neurons, endogenous tau expression, and AD brain-derived competent tau species, offering a more physiologically relevant platform to study tau pathobiology.
tau蛋白病理生物学已成为阿尔茨海默病（AD）进展的关键潜在因素；然而，人类神经元模型一直难以重现所观察到的tau蛋白现象。在此，我们旨在利用人类诱导多能干细胞（hiPSC）技术确定在功能性神经元中实现内源性tau蛋白聚集的最低要求。接种来自AD脑的有活性的tau蛋白物种或重组tau蛋白纤维的优化的hiPSC衍生皮质神经元，其不溶性内源性tau蛋白聚集体增加。重要的是，野生型和突变型hiPSC神经元表现出独特的聚集倾向，这取决于种子菌株而非重复结构域的特性，这表明受体tau蛋白的成功模板化可能由种子的独特构象驱动。本文提出的模型首次成功展示了将人类神经元、内源性tau蛋白表达和来自AD脑的有活性的tau蛋白物种相结合，为研究tau蛋白病理生物学提供了一个更具生理相关性的平台。
