LRP1 is a master regulator of tau uptake and spread

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 and Kenneth S. Kosik ()
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Jennifer N. Rauch: University of California
Gabriel Luna: University of California
Elmer Guzman: University of California
Morgane Audouard: University of California
Collin Challis: California Institute of Technology
Youssef E. Sibih: University of California
Carolina Leshuk: University of California
Israel Hernandez: University of California
Susanne Wegmann: German Center for Neurodegenerative Diseases (DZNE)
Bradley T. Hyman: Harvard Medical School
Viviana Gradinaru: California Institute of Technology
Martin Kampmann: University of California
Kenneth S. Kosik: University of California

Nature, 2020, vol. 580, issue 7803, 381-385

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2156-5

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