Porayette Prashob, Kaltcheva Maria M, Perry George, Butler Tracy, Vadakkadath Meethal Sivan, Atwood Craig S
Geriatric Research, Education and Clinical Center, Veterans Administration Hospital and Department of Medicine, University of Wisconsin, Madison, WI, USA.
Department of Neuroscience, Development and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, USA.
J Alzheimers Dis Rep. 2025 Sep 17;9:25424823251370643. doi: 10.1177/25424823251370643. eCollection 2025 Jan-Dec.
Tau phosphorylation is associated with neuronal division and differentiation in the fetal brain, in neuroblastoma cells, in the hibernating brains of ground squirrels and black bears, and in post-mitotic neurons in the Alzheimer's disease (AD) brain. The disassembly of the rigid microtubule structure of neurons for neuronal division and neurite remodeling requires the removal of the microtubule stabilizing protein tau via its phosphorylation.
To determine if tau phosphorylation is required during neural embryogenesis.
Using an human model of early embryonic development, human embryonic stem cells (hESC) were differentiated into embryoid bodies (EBs; akin to an early blastocyst) and then into neuroectodermal rosettes (akin to a rudimentary neural tube containing neuroectodermal precursor cells) upon treatment with progesterone. The neuroectodermal rosettes were then treated with and without LiCl (Cdk5 inhibitor) or roscovitine (GSK-3β inhibitor) and assayed for the expression of tau, P-tau, nestin (an early marker of neurogenesis), Cdk5 and GSK-3β.
Tau was not expressed in hESC, but tau expression and its phosphorylation increase upon progesterone-induced differentiation of hESC into neuroectodermal rosettes. Both Cdk5 and GSK-3β, enzymes associated with tau phosphorylation, were expressed in hESCs, EBs, and neuroectodermal rosettes. The GSK-3β inhibitor LiCl, but not the Cdk-5 inhibitor roscovitine, prevented tau phosphorylation and nestin expression and the formation of neuroectodermal precursor cells.
These preliminary results suggest that progesterone induces tau expression and its phosphorylation during the differentiation of neuroectodermal rosettes from hESC and suggest that tau and its phosphorylation is obligatory for neuronal precursor cell mitosis. The parallels between neural embryogenesis and neurodegeneration are discussed in the context of tau phosphorylation and the aberrant re-entry of neurons into the cell cycle in AD.
在胎儿大脑、神经母细胞瘤细胞、地松鼠和黑熊的冬眠大脑以及阿尔茨海默病（AD）大脑的有丝分裂后神经元中，tau蛋白磷酸化与神经元的分裂和分化有关。神经元为进行细胞分裂和轴突重塑而使僵硬的微管结构解体，这需要通过tau蛋白磷酸化来去除微管稳定蛋白tau。
确定在神经胚胎发生过程中是否需要tau蛋白磷酸化。
利用人类早期胚胎发育模型，将人类胚胎干细胞（hESC）分化为胚状体（EBs，类似于早期囊胚），然后在用黄体酮处理后分化为神经外胚层玫瑰花结（类似于含有神经外胚层前体细胞的原始神经管）。然后，对神经外胚层玫瑰花结进行氯化锂（Cdk5抑制剂）或roscovitine（GSK-3β抑制剂）处理或不处理，并检测tau、P-tau、巢蛋白（神经发生的早期标志物）、Cdk5和GSK-3β的表达。
tau蛋白在hESC中不表达，但在黄体酮诱导hESC分化为神经外胚层玫瑰花结时，tau蛋白表达及其磷酸化增加。与tau蛋白磷酸化相关的酶Cdk5和GSK-3β在hESC、EBs和神经外胚层玫瑰花结中均有表达。GSK-3β抑制剂氯化锂可阻止tau蛋白磷酸化、巢蛋白表达以及神经外胚层前体细胞的形成，而Cdk-5抑制剂roscovitine则无此作用。
这些初步结果表明，黄体酮在hESC分化为神经外胚层玫瑰花结的过程中诱导tau蛋白表达及其磷酸化，提示tau蛋白及其磷酸化对于神经元前体细胞的有丝分裂是必不可少的。本文在tau蛋白磷酸化以及AD中神经元异常重新进入细胞周期的背景下，讨论了神经胚胎发生与神经退行性变之间的相似性。
