Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (M_i) or seed-competent (M_s) conformational ensembles and that M_s encodes strains, that is, unique, self-replicating, biologically active assemblies. It is unknown if disease begins with M_s formation followed by fibril assembly or if M_s derives from fibrils and is therefore an epiphenomenon. Here, we studied a tauopathy mouse model (PS19) that expresses full-length mutant human (1N4R) tau (P301S). Insoluble tau seeding activity appeared at 2 months of age and insoluble tau protein assemblies by immunoblot at 3 months. Tau monomer from mice aged 1 to 6 weeks, purified using size-exclusion chromatography, contained soluble seeding activity at 4 weeks, before insoluble material or larger assemblies were observed, with assemblies ranging from n = 1 to 3 tau units. By 5 to 6 weeks, large soluble assemblies had formed. This indicated that the first detectable pathological forms of tau were in fact M_s. We next examined posttranslational modifications of tau monomer from 1 to 6 weeks. We detected no phosphorylation unique to M_s in PS19 or human Alzheimer’s disease brains. We conclude that tauopathy begins with formation of the M_s monomer, whose activity is phosphorylation independent. M_s then self assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from M_i to M_s thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for the origins of tauopathy in humans.

Tau 聚集成有序的组件会导致神经退行性 tau 病变。我们之前报道过 tau 单体存在于惰性 (M _i ) 或种子能力 (M _s ) 构象集合中，并且 M _s编码菌株，即独特的、自我复制的、具有生物活性的组件。尚不清楚疾病是从 M _s形成开始，然后是原纤维组装，还是 M _s来源于原纤维，因此是一种附带现象。在这里，我们研究了表达全长突变人类 (1N4R) tau (P301S) 的 tauopathy 小鼠模型 (PS19)。不溶性 tau 播种活性在 2 个月大时出现，不溶性 tau 蛋白组装体在 3 个月时通过免疫印迹显示。来自 1 至 6 周龄小鼠的 Tau 单体，使用尺寸排阻色谱法纯化，在 4 周时含有可溶性接种活性，然后观察到不溶性材料或更大的组件，组件范围从 n = 1 到 3 个 tau 单位。到 5 到 6 周时，已经形成了大的可溶性装配体。这表明第一个可检测到的 tau 病理形式实际上是 M _s。我们接下来从 1 到 6 周检查了 tau 单体的翻译后修饰。_{我们没有检测到 M s}特有的磷酸化在 PS19 或人类阿尔茨海默病的大脑中。我们得出结论，τ蛋白病始于 M _s单体的形成，其活性与磷酸化无关。M _s然后在形成不溶性原纤维之前自组装形成低聚物。因此，tau 单体从 M _i到 M _s的转化构成了该小鼠模型中 tau 病变起始的第一个可检测步骤，对人类 tau 病变的起源具有明显的意义。