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Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

Author

Listed:
  • Cameron S. McAlpine

    (Massachusetts General Hospital and Harvard Medical School
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Joseph Park

    (Massachusetts General Hospital and Harvard Medical School)

  • Ana Griciuc

    (Massachusetts General Hospital and Harvard Medical School)

  • Eunhee Kim

    (Massachusetts General Hospital and Harvard Medical School)

  • Se Hoon Choi

    (Massachusetts General Hospital and Harvard Medical School)

  • Yoshiko Iwamoto

    (Massachusetts General Hospital and Harvard Medical School)

  • Máté G. Kiss

    (Massachusetts General Hospital and Harvard Medical School)

  • Kathleen A. Christie

    (Massachusetts General Hospital and Harvard Medical School)

  • Claudio Vinegoni

    (Massachusetts General Hospital and Harvard Medical School)

  • Wolfram C. Poller

    (Massachusetts General Hospital and Harvard Medical School
    Icahn School of Medicine at Mount Sinai)

  • John E. Mindur

    (Massachusetts General Hospital and Harvard Medical School)

  • Christopher T. Chan

    (Massachusetts General Hospital and Harvard Medical School)

  • Shun He

    (Massachusetts General Hospital and Harvard Medical School)

  • Henrike Janssen

    (Massachusetts General Hospital and Harvard Medical School)

  • Lai Ping Wong

    (Massachusetts General Hospital
    Harvard Medical School)

  • Jeffrey Downey

    (Massachusetts General Hospital and Harvard Medical School)

  • Sumnima Singh

    (Massachusetts General Hospital and Harvard Medical School)

  • Atsushi Anzai

    (Massachusetts General Hospital and Harvard Medical School)

  • Florian Kahles

    (Massachusetts General Hospital and Harvard Medical School)

  • Mehdi Jorfi

    (Massachusetts General Hospital and Harvard Medical School)

  • Paolo Fumene Feruglio

    (University of Verona)

  • Ruslan I. Sadreyev

    (Massachusetts General Hospital
    Massachusetts General Hospital and Harvard Medical School)

  • Ralph Weissleder

    (Massachusetts General Hospital and Harvard Medical School)

  • Benjamin P. Kleinstiver

    (Massachusetts General Hospital and Harvard Medical School)

  • Matthias Nahrendorf

    (Massachusetts General Hospital and Harvard Medical School)

  • Rudolph E. Tanzi

    (Massachusetts General Hospital and Harvard Medical School)

  • Filip K. Swirski

    (Massachusetts General Hospital and Harvard Medical School
    Icahn School of Medicine at Mount Sinai)

Abstract

Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD.

Suggested Citation

  • Cameron S. McAlpine & Joseph Park & Ana Griciuc & Eunhee Kim & Se Hoon Choi & Yoshiko Iwamoto & Máté G. Kiss & Kathleen A. Christie & Claudio Vinegoni & Wolfram C. Poller & John E. Mindur & Christophe, 2021. "Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease," Nature, Nature, vol. 595(7869), pages 701-706, July.
    • Handle: RePEc:nat:nature:v:595:y:2021:i:7869:d:10.1038_s41586-021-03734-6
    DOI: 10.1038/s41586-021-03734-6
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    Cited by:

    1. Xingyu Zhang & Li Tang & Jiaolong Yang & Lanxia Meng & Jiehui Chen & Lingyan Zhou & Jiangyu Wang & Min Xiong & Zhentao Zhang, 2023. "Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Timothy F. Shay & Seongmin Jang & Tyler J. Brittain & Xinhong Chen & Beth Walker & Claire Tebbutt & Yujie Fan & Damien A. Wolfe & Cynthia M. Arokiaraj & Erin E. Sullivan & Xiaozhe Ding & Ting-Yu Wang , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Jiyeon Lee & Haeryung Lee & Hyein Lee & Miram Shin & Min-Gi Shin & Jinsoo Seo & Eun Jeong Lee & Sun Ah Park & Soochul Park, 2023. "ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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