Systematic characterization of brain cellular crosstalk reveals a novel role for SEMA6D in TREM2-associated microglial function in Alzheimer’s disease

Abstract

AbstractDisrupted cross-cellular signaling (cellular crosstalk) is implicated in Alzheimer’s disease (AD) and neurodegeneration. Previous studies were restricted to specific cell types and pathways, precluding a comprehensive understanding of cellular crosstalk in AD. Here, we systematically characterized crosstalk interactions using single-nucleus transcriptional profiles from 67 clinically and neuropathologically well-characterized controls and AD brain donors. Crosstalk between microglia and neurons involved known AD risk genes as ligands or receptors. Reconstruction of the gene networks mediating this crosstalk revealed additional known AD risk genes perturbed in microglia. We identified a novel interaction between neuronal SEMA6D and a microglial regulatory sub-network involvingTREM2that is disrupted in AD and activated in the vicinity of Aβ plaques andSEMA6D-expressingcells. Using CRISPR-modified human induced pluripotent stem cell-derived microglia, we demonstrated that SEMA6D activates microglia in a TREM2-dependent manner. Together, we show that characterizing cellular crosstalk networks yields new insights into AD biology.