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Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release

Author

Listed:
  • Max Adrian

    (Genentech, Inc.
    Genentech, Inc.)

  • Martin Weber

    (Genentech, Inc.)

  • Ming-Chi Tsai

    (Genentech, Inc.)

  • Caspar Glock

    (Genentech Inc.)

  • Olga I. Kahn

    (Genentech, Inc.)

  • Lilian Phu

    (Department of Microchemistry, Proteomics and Lipidomics)

  • Tommy K. Cheung

    (Department of Microchemistry, Proteomics and Lipidomics)

  • William J. Meilandt

    (Genentech, Inc.)

  • Christopher M. Rose

    (Department of Microchemistry, Proteomics and Lipidomics)

  • Casper C. Hoogenraad

    (Genentech, Inc.)

Abstract

Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identifies microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We find that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally-anchored array to facilitate efficient cytokine trafficking and release. We identify cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescues tau and amyloid fibril-induced morphology changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses.

Suggested Citation

  • Max Adrian & Martin Weber & Ming-Chi Tsai & Caspar Glock & Olga I. Kahn & Lilian Phu & Tommy K. Cheung & William J. Meilandt & Christopher M. Rose & Casper C. Hoogenraad, 2023. "Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41891-6
    DOI: 10.1038/s41467-023-41891-6
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    1. Laetitia Weinhard & Giulia Bartolomei & Giulia Bolasco & Pedro Machado & Nicole L. Schieber & Urte Neniskyte & Melanie Exiga & Auguste Vadisiute & Angelo Raggioli & Andreas Schertel & Yannick Schwab &, 2018. "Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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