LPS causes a transcriptional shift in iPSC-microglia similar to an activated state from genetic mouse models of AD

Alzheimer’s disease (AD) is the most common form of dementia and risk-influencing genetics implicates microglia and neuroimmunity in the pathogenesis of AD. iPSC-microglia are increasingly used as a model of AD but the relevance of common immune stimuli to model AD is unclear. We performed a detailed cross-comparison over time on the effects of combinatory stimulation of iPSC-microglia, and in particular their relevance to AD. We used single cell RNA-seq to measure the transcriptional response of iPSC-microglia after 24 and 48h of stimulation with PGE2 or LPS+IFN-γ either alone or in combination with ATPγS. We observed a shared core transcriptional response of iPSC-microglia to ATPγS and to LPS+IFN-γ, suggestive of a convergent mechanism of action. Across all conditions we observed a significant overlap and functional links to genes that change their expression levels in human microglia from AD patients. Using a data-led approach, we identify a common axis of transcriptomic change across AD genetic mouse model microglia and show that only LPS provokes a transcriptional response along this axis in mouse microglia and LPS+IFN-γ in human iSPC-microglia. Single cell expression profiles for iPSC derived microglia from 4 biological replicates across 8 different conditions. iPSC- microglia were exposed to individual and combined stimuli and their transcriptional profiled measured after 24 or 48 hours. The eight conditions included Control, ATPgS 24h, LPS+IFNg 24h, PGE2 24h, LPS+IFNg 48h, PGE2 48h, LPS+IFN 48h ATPgS 24h, PGE2 48h ATPgS 24h.