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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

Author

Listed:
  • Elizabeth Spangenberg

    (University of California Irvine (UCI))

  • Paul L. Severson

    (Plexxikon Inc)

  • Lindsay A. Hohsfield

    (University of California Irvine (UCI))

  • Joshua Crapser

    (University of California Irvine (UCI))

  • Jiazhong Zhang

    (Plexxikon Inc)

  • Elizabeth A. Burton

    (Plexxikon Inc)

  • Ying Zhang

    (Plexxikon Inc)

  • Wayne Spevak

    (Plexxikon Inc)

  • Jack Lin

    (Plexxikon Inc)

  • Nicole Y. Phan

    (University of California Irvine (UCI))

  • Gaston Habets

    (Plexxikon Inc)

  • Andrey Rymar

    (Plexxikon Inc)

  • Garson Tsang

    (Plexxikon Inc)

  • Jason Walters

    (Plexxikon Inc)

  • Marika Nespi

    (Plexxikon Inc)

  • Parmveer Singh

    (Plexxikon Inc)

  • Stephanie Broome

    (Plexxikon Inc)

  • Prabha Ibrahim

    (Plexxikon Inc)

  • Chao Zhang

    (Plexxikon Inc)

  • Gideon Bollag

    (Plexxikon Inc)

  • Brian L. West

    (Plexxikon Inc)

  • Kim N. Green

    (University of California Irvine (UCI))

Abstract

Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.

Suggested Citation

  • Elizabeth Spangenberg & Paul L. Severson & Lindsay A. Hohsfield & Joshua Crapser & Jiazhong Zhang & Elizabeth A. Burton & Ying Zhang & Wayne Spevak & Jack Lin & Nicole Y. Phan & Gaston Habets & Andrey, 2019. "Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model," Nature Communications, Nature, vol. 10(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11674-z
    DOI: 10.1038/s41467-019-11674-z
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    Cited by:

    1. Alicia Bedolla & Elliot Wegman & Max Weed & Messiyah K. Stevens & Kierra Ware & Aditi Paranjpe & Anastasia Alkhimovitch & Igal Ifergan & Aleksandr Taranov & Joshua D. Peter & Rosa Maria Salazar Gonzal, 2024. "Adult microglial TGFβ1 is required for microglia homeostasis via an autocrine mechanism to maintain cognitive function in mice," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    2. Laura K. Hamilton & Gaël Moquin-Beaudry & Chenicka L. Mangahas & Federico Pratesi & Myriam Aubin & Anne Aumont & Sandra E. Joppé & Alexandre Légiot & Annick Vachon & Mélanie Plourde & Catherine Mounie, 2022. "Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Yannick Fotio & Alex Mabou Tagne & Erica Squire & Hye-lim Lee & Connor M. Phillips & Kayla Chang & Faizy Ahmed & Andrew S. Greenberg & S. Armando Villalta & Vanessa M. Scarfone & Gilberto Spadoni & Ma, 2024. "NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Suvra Nath & Jose C. Martínez Santamaría & Yu-Hsuan Chu & James S. Choi & Pasquale Conforti & Jia-Di Lin & Roman Sankowski & Lukas Amann & Christos Galanis & Kexin Wu & Sachin S. Deshpande & Andreas V, 2024. "Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Rasmus Berglund & Yufei Cheng & Eliane Piket & Milena Z. Adzemovic & Manuel Zeitelhofer & Tomas Olsson & Andre Ortlieb Guerreiro-Cacais & Maja Jagodic, 2024. "The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Noah R. Johnson & Peng Yuan & Erika Castillo & T. Peter Lopez & Weizhou Yue & Annalise Bond & Brianna M. Rivera & Miranda C. Sullivan & Masakazu Hirouchi & Kurt Giles & Atsushi Aoyagi & Carlo Condello, 2023. "CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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