美国加州大学Kenneth S. Kosik研究组的研究发现，低密度脂蛋白受体相关蛋白1（LRP1）是tau蛋白内吞和扩散的主要调控因子。2020年4月1日，《自然》在线发表了这项成果。

研究人员发现LRP1控制tau的内吞及其随后的传播。降低LRP1可以显著降低H4神经胶质瘤细胞和诱导多能干细胞衍生的神经元中tau的内吞。tau和LRP1之间的相互作用是由tau微管蛋白结合重复结构域中的赖氨酸残基介导。

此外，在tau传播的小鼠模型中，LRP1的下调可有效减少tau在神经元之间的传播。该研究揭示LRP1是调节tau在大脑中扩散的关键因子，因此LRP1可以作为治疗与tau扩散和聚集相关疾病的潜在靶点。

据悉，蛋白质聚集体的扩散是许多神经退行性疾病进展的共同特征。与微管相关的蛋白tau在几种痴呆症的发病机理中起着关键作用，包括阿尔茨海默氏病、额颞痴呆和慢性创伤性脑病。

这些疾病的进展特征是与临床严重性相关的可预测蛋白质聚集体的扩散和沉积。之前的研究和补充实验研究表明，tau可以通过模板将错误折叠和聚集的蛋白传递给新生细胞，从而以朊病毒样的方式传播。然而，尽管tau的传播已得到广泛的研究，但是对其潜在的细胞机制仍知之甚少。

附：英文原文

Title: LRP1 is a master regulator of tau uptake and spread

Author: Jennifer N. Rauch, Gabriel Luna, Elmer Guzman, Morgane Audouard, Collin Challis, Youssef E. Sibih, Carolina Leshuk, Israel Hernandez, Susanne Wegmann, Bradley T. Hyman, Viviana Gradinaru, Martin Kampmann, Kenneth S. Kosik

Issue&Volume: 2020-04-01

Abstract: 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 studies3,4 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.

DOI: 10.1038/s41586-020-2156-5

Source: https://www.nature.com/articles/s41586-020-2156-5