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Single-cell analysis reveals inflammatory interactions driving macular degeneration

Author

Listed:
  • Manik Kuchroo

    (Yale University)

  • Marcello DiStasio

    (Yale University)

  • Eric Song

    (Yale University)

  • Eda Calapkulu

    (Yale University)

  • Le Zhang

    (Yale University
    Yale University)

  • Maryam Ige

    (Yale School of Medicine)

  • Amar H. Sheth

    (Yale School of Medicine)

  • Abdelilah Majdoubi

    (Yale University)

  • Madhvi Menon

    (University of Manchester)

  • Alexander Tong

    (Yale University)

  • Abhinav Godavarthi

    (Yale University)

  • Yu Xing

    (Yale University)

  • Scott Gigante

    (Yale University)

  • Holly Steach

    (Yale University School of Medicine)

  • Jessie Huang

    (Yale University)

  • Guillaume Huguet

    (Mila—Quebec AI institute
    Université de Montréal)

  • Janhavi Narain

    (Rutgers University)

  • Kisung You

    (Yale University)

  • George Mourgkos

    (Yale University)

  • Rahul M. Dhodapkar

    (Yale School of Medicine)

  • Matthew J. Hirn

    (Michigan State University
    Michigan State University)

  • Bastian Rieck

    (ETH Zurich)

  • Guy Wolf

    (Mila—Quebec AI institute
    Université de Montréal)

  • Smita Krishnaswamy

    (Yale University
    Yale University)

  • Brian P. Hafler

    (Yale University
    Yale University
    Broad Institute of MIT and Harvard)

Abstract

Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer’s disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1β which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.

Suggested Citation

  • Manik Kuchroo & Marcello DiStasio & Eric Song & Eda Calapkulu & Le Zhang & Maryam Ige & Amar H. Sheth & Abdelilah Majdoubi & Madhvi Menon & Alexander Tong & Abhinav Godavarthi & Yu Xing & Scott Gigant, 2023. "Single-cell analysis reveals inflammatory interactions driving macular degeneration," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37025-7
    DOI: 10.1038/s41467-023-37025-7
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    References listed on IDEAS

    as
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