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Kuchroo, Manik; DiStasio, Marcello; Song, Eric; Calapkulu, Eda; Zhang, Le; Ige, Maryam; Sheth, Amar H; Majdoubi, Abdelilah; Menon, Madhvi; Tong, Alexander; Godavarthi, Abhinav; Xing, Yu; Gigante, Scott; Steach, Holly; Huang, Jessie; Huguet, Guillaume; Narain, Janhavi; You, Kisung; Mourgkos, George; Dhodapkar, Rahul M; Hirn, Matthew J; Rieck, Bastian; Wolf, Guy; Krishnaswamy, Smita; Hafler, Brian P
Nature communications, 05/2023, Volume: 14, Issue: 1Journal Article
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.
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