The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies—including Alzheimer’s disease, frontotemporal dementia and chronic traumatic encephalopathy¹. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity². This observation and complementary experimental studies^3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.

疾病进展过程中蛋白质聚集体的扩散是许多神经退行性疾病的共同主题。微管相关蛋白 tau 在被称为 tau 病的多种形式的痴呆的发病机制中发挥着核心作用，包括阿尔茨海默病、额颞叶痴呆和慢性创伤性脑病¹。这些疾病的进展的特点是蛋白质聚集体以可预测的模式连续扩散和沉积，与临床严重程度相关²。这种观察和补充实验研究^3,4已经表明 tau 可以以类似朊病毒的方式传播，通过传递到它模板错误折叠和聚集的幼稚细胞。然而，尽管 tau 的传播已被广泛研究，但其潜在的细胞机制仍然知之甚少。在这里，我们显示低密度脂蛋白受体相关蛋白 1 (LRP1) 控制 tau 的内吞作用及其随后的扩散。LRP1 的敲低显着降低了 H4 神经胶质瘤细胞和诱导的多能干细胞衍生神经元中的 tau 摄取。tau 和 LRP1 之间的相互作用是由 tau 的微管结合重复区中的赖氨酸残基介导的。此外，LRP1 的下调在 tau 扩散的体内小鼠模型中，发现有效减少 tau 在神经元之间的传播。我们的研究结果确定 LRP1 是 tau 在大脑中扩散的关键调节因子，因此是治疗涉及 tau 扩散和聚集的疾病的潜在目标。