Single-cell multiomics reveals microglia–neuron granulin signaling associated with brain aging
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Aging is the primary risk factor for neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE). Although recent single-cell studies provided insights into cellular heterogeneity in the aging brain, how aging reshapes regulatory programs and intercellular communication in brain remains limited. Here, we performed an integrated single-cell multiomic analysis of young and aged mouse brains by combining transcriptomic and chromatin accessibility profiling. Our analysis revealed aging-associated remodeling of neuronal–glial communication, including increased granulin (GRN) signaling from microglia to neuronal populations and elevated expression of its receptor Sort1 in the aged brain. In addition, specific neuronal subtypes exhibited regulatory shifts characterized by enrichment of Fos/Jun transcription factor motifs and increased chromatin accessibility at the Sort1 promoter. These findings identify aging-associated regulatory pathways linking microglial signaling and neuronal transcriptional programs and provide insights into mechanisms that may increase susceptibility to neurodegeneration.
