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Received: 8 October 2019
Accepted: 27 February 2020
Published online: 1 April 2020
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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 receptorrelated 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.
Recent work has highlighted the importance of heparan sulfate proteoglycans (HSPGs) in tau uptake5,6, and low-density lipoprotein receptors (LDLRs) are known to work in conjunction with HSPGs7. On the basis of this knowledge, we set out to test whether any members of the LDLR family could influence tau internalization. Using CRISPR interference (CRISPRi) technology, the expression of genes encoding various members of the LDLR family (LRP1, LRP1B, LRP2, LRP5, LRP8, LDLR and VLDLR; Extended Data Fig. 1c) was efficiently repressed in H4 neuroglioma cells, and the ability of these cells to endocytose monomeric tau was assessed5 (Fig. 1a, b). Genetic silencing of LRP1 almost completely blocked the uptake of full-length soluble monomeric tau (2N4R isoform), whereas no significant effect was found upon silencing any other LDLR family member (Fig. 1b). Different mechanisms have been proposed for...