Lipopolysaccharide distinctively alters human microglia transcriptomes to resemble microglia from Alzheimer's disease mouse models

Alzheimer's disease (AD) is the most common form of dementia, and risk-influencing genetics implicates microglia and neuroimmunity in the pathogenesis of AD. Induced pluripotent stem cell (iPSC)-derived microglia (iPSC-microglia) are increasingly used as a model of AD, but the relevance of historical 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 sequencing to measure the transcriptional response of iPSC-microglia after 24 h and 48 h of stimulation with prostaglandin E2 (PGE(2)) or lipopolysaccharide (LPS)+interferon gamma (IFN-gamma), either alone or in combination with ATP gamma S. We observed a shared core transcriptional response of iPSCmicroglia to ATP gamma S and to LPS+IFN-gamma, suggestive of a convergent mechanism of action. Across all conditions, we observed a significant overlap, although directional inconsistency to genes that change their expression levels in human microglia from AD patients. Using a dataled approach, we identify a common axis of transcriptomic change across AD genetic mouse models of microglia and show that only LPS provokes a transcriptional response along this axis in mouse microglia and LPS+IFN-gamma in human iPSC-microglia.

Automated summary

This study investigated the relevance of different immune stimuli on the transcriptional response of iPSC-microglia, a model of Alzheimer's disease (AD). The results showed a shared core transcriptional response to ATP gamma S and LPS+IFN-gamma, indicating a convergent mechanism of action. However, there was directional inconsistency in the expression levels of genes related to these stimuli in human microglia from AD patients.