Harvard Medical School, Boston, Massachusetts 02115
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114-2696.
J Neurosci. 2021 May 12;41(19):4335-4348. doi: 10.1523/JNEUROSCI.2590-20.2021. Epub 2021 Apr 23.
Tau aggregation within neurons is a critical feature of Alzheimer's disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the formation of tau aggregates in a prion-like manner and propagate through connected neurons during the progression of disease. Both soluble and aggregated forms of tau are thought to have neurotoxic properties. In addition, different strains of misfolded tau may cause differential neurotoxicity. In this work, we present an accelerated human neuronal model of tau-induced neurotoxicity that incorporates both soluble tau species and tau aggregation. Using patient-derived induced pluripotent stem cell (iPSC) neurons expressing a tau aggregation biosensor, we develop a cell culture system that allows continuous assessment of both induced tau aggregation and neuronal viability at single-cell resolution for periods of >1 week. We show that exogenous tau "seed" uptake, as measured by tau repeat domain (TauRD) reporter aggregation, increases the risk for subsequent neuronal death These results are the first to directly visualize neuronal TauRD aggregation and subsequent cell death in single human iPSC neurons. Specific morphologic strains or patterns of TauRD aggregation are then identified and associated with differing neurotoxicity. Furthermore, we demonstrate that familial AD iPSC neurons expressing the PSEN1 L435F mutation exhibit accelerated TauRD aggregation kinetics and a tau strain propagation bias when compared with control iPSC neurons. Neuronal intracellular aggregation of the microtubule binding protein tau occurs in Alzheimer's disease and related neurodegenerative tauopathies. Tau aggregates are believed to spread from neuron to neuron via prion-like misfolded tau seeds. Our work develops a human neuronal live-imaging system to visualize seeded tau aggregation and tau-induced neurotoxicity within single neurons. Using an aggregation-sensing tau reporter, we find that neuronal uptake and propagation of tau seeds reduces subsequent survival. In addition, human induced pluripotent stem cell (iPSC) neurons carrying an Alzheimer's disease-causing mutation in presenilin-1 undergo tau seeding more rapidly than control iPSC neurons. However, they do not show subsequent differences in neuronal survival. Finally, specific morphologies of tau aggregates are associated with increased neurotoxicity.
神经元内的 Tau 聚集是阿尔茨海默病（AD）和相关 Tau 病的一个关键特征。据信，可溶性病理性 Tau 物种以类朊病毒的方式为 Tau 聚集的形成提供种子，并在疾病进展过程中通过连接的神经元传播。可溶性和聚集形式的 Tau 都被认为具有神经毒性。此外，不同的错误折叠 Tau 株可能导致不同的神经毒性。在这项工作中，我们提出了一种加速的人类神经元 Tau 诱导神经毒性模型，该模型结合了可溶性 Tau 物种和 Tau 聚集。使用表达 Tau 聚集生物传感器的患者来源诱导多能干细胞（iPSC）神经元，我们开发了一种细胞培养系统，该系统允许以单细胞分辨率连续评估诱导的 Tau 聚集和神经元活力超过 1 周的时间。我们表明，外源性 Tau“种子”摄取，如 Tau 重复结构域（TauRD）报告基因聚集所测量的，增加了随后神经元死亡的风险。这些结果是首次直接在单个人类 iPSC 神经元中可视化神经元 TauRD 聚集和随后的细胞死亡。然后确定特定的形态菌株或 TauRD 聚集模式，并与不同的神经毒性相关。此外，我们证明，与对照 iPSC 神经元相比，表达 PSEN1 L435F 突变的家族性 AD iPSC 神经元表现出加速的 TauRD 聚集动力学和 Tau 株传播偏向性。微管结合蛋白 Tau 在阿尔茨海默病和相关神经退行性 Tau 病中发生神经元内聚集。据信，tau 聚集物通过类朊病毒错误折叠的 tau 种子从一个神经元传播到另一个神经元。我们的工作开发了一种人类神经元活体成像系统，用于在单个神经元中可视化接种的 Tau 聚集和 Tau 诱导的神经毒性。使用聚集感应 Tau 报告基因，我们发现神经元摄取和传播 Tau 种子会降低随后的存活。此外，携带早老素 1 中导致阿尔茨海默病的突变的人类诱导多能干细胞（iPSC）神经元比对照 iPSC 神经元更容易发生 Tau 接种，但随后神经元存活没有差异。最后，特定形态的 Tau 聚集物与增加的神经毒性相关。
