Overview

• Researchers mapped cell-to-cell communication in human Alzheimer’s brains using single-nucleus RNA sequencing from 67 donors, computational network reconstruction, spatial transcriptomics, and tissue immunostaining.
• Spatial analyses showed the SEMA6D-TREM2 network is activated near amyloid-beta plaques, with SEMA6D colocalizing with TREM2-positive microglia.
• Plaque-proximal SEMA6D levels declined with advancing disease stage, correlating with reduced microglial activation near plaques.
• Functional assays with human iPSC-derived microglia showed SEMA6D triggers microglial activation and amyloid-beta phagocytosis in a TREM2-dependent manner.
• Published in Science Translational Medicine, the work highlights membrane receptor-ligand pathways as promising but still preclinical therapeutic targets.