Single-cell analysis reveals inflammatory interactions driving macular degeneration

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 Gigante, Holly Steach, Jessie Huang, Guillaume Huguet, Janhavi Narain, Kisung You, George Mourgkos, Rahul M. Dhodapkar, Matthew J. Hirn, Bastian Rieck, Guy Wolf, Smita Krishnaswamy () and Brian P. Hafler ()
Additional contact information
Manik Kuchroo: Yale University
Marcello DiStasio: Yale University
Eric Song: Yale University
Eda Calapkulu: Yale University
Le Zhang: 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
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
Bastian Rieck: ETH Zurich
Guy Wolf: Mila—Quebec AI institute
Smita Krishnaswamy: Yale University
Brian P. Hafler: Yale University

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37025-7

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