The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer’s disease^1,2, Pick’s disease³, chronic traumatic encephalopathy⁴ and corticobasal degeneration⁵ are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer’s disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities—as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.

tau 蛋白有序组装成细丝是几种神经退行性疾病的特征，称为 tau 病变。先前有报道称，通过冷冻电子显微镜，可以看到阿尔茨海默病^1,2、皮克病³、慢性创伤性脑病⁴和皮质基底节变性^{5的 tau 丝结构}是不同的。在这里，我们表明进行性核上性麻痹 (PSP) 的 tau 丝结构定义了一个新的三层折叠。此外，来自球状胶质细胞 tau 病变的 tau 丝结构与来自 PSP 的相似。嗜银粒病 (AGD) 的 tau 丝皱襞不同，而是类似于皮质基底节变性的四层皱襞。在与衰老相关的 tau 星形胶质细胞病中也观察到 AGD 倍数。来自MAPT内含子 10 中 +3 或 +16 位的遗传突变病例的 Tau 原丝结构（微管相关蛋白 tau 基因）也与来自 AGD 的相同，这表明四重复 tau 的相对过量产生可以引起 AGD 折叠。最后，家族性英国痴呆和家族性丹麦痴呆病例的 tau 丝结构与阿尔茨海默病和原发性年龄相关性 tau 病变病例的结构相同。这些发现表明基于丝状折叠对 tau蛋白病进行分级分类，这补充了临床诊断和神经病理学，还允许识别新实体——正如我们在诊断为 PSP 的病例中所展示的那样，但丝状结构介于两者之间球状胶质细胞 tau蛋白病和 PSP。