Single-Cell Profiling Reveals a Common Glial Inflammatory Signature in Neurodegeneration

Age-related macular degeneration (AMD), Alzheimer’s disease (AD), and progressive multiple sclerosis (MS) are neurodegenerative diseases of the central nervous system. Microglial dysregulation contributes to neuronal damage in AD and MS, but the cellular mechanisms driving chronic inflammation and vision loss in AMD remain unclear. We hypothesized that shared microglial activation states contribute to neurodegeneration across diseases and that the human retina could serve as a model to study these mechanisms. To identify cellular drivers of AMD, we performed single-nucleus RNA sequencing on retinal tissue from 11 individuals with AMD and 6 age-matched controls, generating the first single-cell atlas of AMD across disease stages. Disease-associated microglial states were compared with single-nucleus RNA-sequencing data from AD and MS. Using topological data analysis and diffusion geometry, we characterized cell clusters, identified pathogenic populations, and computed differentially expressed genes. Our analysis revealed two activated glial populations enriched in nonexudative AMD: one microglial and one astrocytic subset. These activated microglial states were also present in AD and MS, indicating a conserved inflammatory signature across neurodegenerative conditions. In neovascular AMD, we identified a novel microglia-to-astrocyte signaling axis driving VEGFA expression, a key mediator of pathological angiogenesis, which was validated in vitro and in vivo. This work presents the first single-nucleus transcriptomic atlas of the human retina in AMD and highlights cell-type specific drivers of disease. Our findings reveal shared microglial and astrocytic activation states across neurodegeneration and suggest that microglia-targeted interventions could preserve vision in AMD and slow neurodegeneration in AD and MS.