A study from a team of researchers that includes Marcello DiStasio, MD, PhD, assistant professor of pathology at Yale School of Medicine, and Brian P. Hafler, MD, PhD, assistant professor of ophthalmology & visual science and of pathology, revealed activation of the innate immune system of the retina in age-related macular degeneration (AMD), and convergence between this activation and that seen in neurodegenerative diseases of the brain. The findings provide evidence that the retina, which is the site of damage in AMD—the leading cause of blindness in elderly patients—also represents a system for investigating therapeutic approaches in neurodegenerative diseases.
The study, published recently in Nature Communications, is based on the hypothesis that due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases. That led them to examine whether pathways of disease progression are shared across neurodegenerative conditions.
In the study, the team used single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and six control retinas with no history of retinal disease. In collaboration with Manik Kuchroo (MD ‘22) and Smita Krishnaswamy, PhD, associate professor of genetics and of computer science, they created a new machine-learning pipeline called ‘CATCH,’ based on recent advances in data geometry and topology and identified 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,” the study said. “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.”
The study validated this mechanism using in vitro and in vivo assays in mice, identifying a possible new therapeutic target for AMD as well as other neurodegenerative conditions.
“This set of analyses has clear implications for potential therapeutics for AMD and other neurodegenerative diseases,” the study concluded.