Overview

• A multidisciplinary team combined advanced imaging, single‑nucleus RNA sequencing and the CytoTalk algorithm to reconstruct neuron–glia communication networks in human brains.
• The analysis highlighted a SEMA6D–TREM2 signaling axis that governs microglial activation and amyloid‑clearing functions implicated in Alzheimer’s progression.
• Spatial transcriptomics and immunostaining localized this network near amyloid plaques, with plaque‑proximal SEMA6D declining as disease advances.
• In TREM2‑knockout iPSC‑derived microglia, SEMA6D did not induce activation or Aβ phagocytosis, supporting a TREM2‑dependent mechanism.
• Published in Science Translational Medicine, the study positions cell‑surface crosstalk proteins as potential drug targets but remains preclinical without in vivo or clinical validation.