The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, USA.
Alzheimers Dement. 2010 Mar;6(2):110-7. doi: 10.1016/j.jalz.2009.06.002.
The assembly of tau proteins into paired helical filaments, the building blocks of neurofibrillary tangles, is linked to neurodegeneration in Alzheimer's disease and related tauopathies. A greater understanding of this assembly process could identify targets for the discovery of drugs to treat Alzheimer's disease and related disorders. By using recombinant human tau, we have delineated events leading to the conversion of normal soluble tau into tau fibrils.
Atomic force microscopy and transmission electron microscopy methodologies were used to determine the structure of tau assemblies that formed when soluble tau was incubated with heparin for increasing lengths of time.
Tau initially oligomerizes into spherical nucleation units of 18- to 21-nm diameter that appear to assemble linearly into nascent fibrils. Among the earliest tau fibrils are species that resemble a string of beads formed by linearly aligned spheres that with time seem to coalesce to form straight and twisted ribbon-like filaments, as well as paired helical filaments similar to those found in human tauopathies. An analysis of fibril cross sections at later incubation times revealed three fundamental axial structural features.
By monitoring tau fibrillization, we showed that different tau filament morphologies coexist. Temporal changes in the predominant tau structural species suggest that tau fibrillization involves the generation of structural intermediates, resulting in the formation of tau fibrils with verisimilitude to their authentic human counterparts.
tau 蛋白组装成双螺旋丝，这是神经原纤维缠结的结构基础，与阿尔茨海默病和相关 tau 病的神经退行性变有关。对这一组装过程的深入了解可以确定靶点，从而发现治疗阿尔茨海默病和相关疾病的药物。通过使用重组人 tau，我们描绘了导致正常可溶性 tau 转化为 tau 纤维的过程。
原子力显微镜和透射电子显微镜方法用于确定可溶性 tau 与肝素孵育不同时间后形成的 tau 组装体的结构。
tau 最初寡聚形成 18-21nm 直径的球形核形成单位，这些单位似乎在线性组装成新生纤维。最早的 tau 纤维中存在一些类似珠子串的物种，这些珠子由线性排列的球体形成，随着时间的推移，它们似乎融合在一起，形成直的和扭曲的带状纤维，以及类似于人类 tau 病中发现的双螺旋丝。对后期孵育时间的纤维横截面进行分析，揭示了三个基本的轴向结构特征。
通过监测 tau 的纤维化过程，我们表明不同的 tau 纤维形态共存。tau 主要结构物种的时间变化表明 tau 纤维化涉及结构中间产物的产生，导致形成与真实 tau 纤维相似的 tau 纤维。
