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Published April 16, 2020 | Supplemental Material
Journal Article Open

LRP1 is a master regulator of tau uptake and spread

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 encephalopathy. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity. This observation and complementary experimental studies 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.

Additional Information

© 2020 Springer Nature Limited. Received 08 October 2019; Accepted 27 February 2020; Published 01 April 2020. This study was funded by the National Institutes of Health (NIH), K99 AG064116 (J.N.R.), DP2 GM119139 (M.K.), R01 AG062359 (M.K.), R56 AG057528 (M.K.), U54 NS 100717 (M.K., K.S.K.), Tau Consortium (M.K., K.S.K.), German Center for Neurodegenerative Diseases (S.W.), Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative (M.K.), Tri-counties Blood Bank (J.N.R.), Dr Miriam and Sheldon G. Adelson Medical Research Foundation (K.S.K.), Larry L. Hillblom Foundation (K.S.K.) and Edward N. & Della L. Thome Memorial Foundation (K.S.K.). We thank the Laboratory for Stem Cell Biology and Engineering at UCSB for use of their flow cytometer, the Neuroscience Research Institute Microscopy Facility for use of their microscopes, J. Dong for help in the early stages of this project and P. Davies for providing the MC-1 antibody. Data availability: Source data are available for graphs plotted in Figs. 1–4 and Extended Data Figs. 1–3. Scans of the full western blot gels can be found in Supplementary Fig. 1. All other data are available from the corresponding author upon reasonable request. Author Contributions: J.N.R. and K.S.K. conceived the study. J.N.R. and K.S.K. designed the study. J.N.R. performed most of the experiments and analysed the data, assisted by G.L., E.G., M.A., C.C., Y.E.S., C.L. and I.H. C.C., V.G., S.W. and B.T.H. provided AAVs used in the study. M.K. provided CRISPRi cell lines. J.N.R. and K.S.K. wrote the manuscript, and all authors discussed the results and commented on the manuscript. Competing interests: K.S.K. is on the Board of Directors of the Rainwater Charitable Trust.

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Created:
August 19, 2023
Modified:
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