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LRP1 is a master regulator of tau uptake and spread

Author

Listed:
  • 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
    Chan Zuckerberg Biohub)

  • Kenneth S. Kosik

    (University of California)

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.

Suggested Citation

  • 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 & M, 2020. "LRP1 is a master regulator of tau uptake and spread," Nature, Nature, vol. 580(7803), pages 381-385, April.
  • Handle: RePEc:nat:nature:v:580:y:2020:i:7803:d:10.1038_s41586-020-2156-5
    DOI: 10.1038/s41586-020-2156-5
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    Citations

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    Cited by:

    1. Vishruth Mullapudi & Jaime Vaquer-Alicea & Vaibhav Bommareddy & Anthony R. Vega & Bryan D. Ryder & Charles L. White & Marc. I. Diamond & Lukasz A. Joachimiak, 2023. "Network of hotspot interactions cluster tau amyloid folds," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Nathaniel S. Chapman & Ruben J. G. Hulswit & Jonna L. B. Westover & Robert Stass & Guido C. Paesen & Elad Binshtein & Joseph X. Reidy & Taylor B. Engdahl & Laura S. Handal & Alejandra Flores & Brian B, 2023. "Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Jiyeon Lee & Julie M. Dimitry & Jong Hee Song & Minsoo Son & Patrick W. Sheehan & Melvin W. King & G. Travis Tabor & Young Ah Goo & Mitchell A. Lazar & Leonard Petrucelli & Erik S. Musiek, 2023. "Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Meihua Jin & Hiroki Shiwaku & Hikari Tanaka & Takayuki Obita & Sakurako Ohuchi & Yuki Yoshioka & Xiaocen Jin & Kanoh Kondo & Kyota Fujita & Hidenori Homma & Kazuyuki Nakajima & Mineyuki Mizuguchi & Hi, 2021. "Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation," Nature Communications, Nature, vol. 12(1), pages 1-22, December.

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