Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.

Tau 聚集是阿尔茨海默病和其他 tau 病的一个明确的组织病理学特征。然而，tau 增殖所涉及的细胞机制仍不清楚。在这里，我们进行了一项公正的定量蛋白质组学研究，以确定与这种 tau 种子特异性相互作用的蛋白质。我们鉴定出 Bassoon (BSN)（一种突触前支架蛋白）是从 tau 蛋白病小鼠模型以及阿尔茨海默病和进行性核上性麻痹死后样本中分离出的 tau 种子的相互作用蛋白。我们发现，BSN 会加剧 tau 蛋白病小鼠和果蝇模型中的 tau 播种和毒性，并且 BSN 下调可减少 tau 扩散和整体疾病病理，从而挽救突触和行为障碍并减少脑萎缩。我们的研究结果加深了人们对 BSN 等相互作用因子如何稳定 tau 种子的理解。抑制 tau 种子相互作用是神经退行性 tau 病的一种潜在的新治疗方法。