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

Dis Model Mech. 2022 Oct 1;15(10):dmm049349. doi: 10.1242/dmm.049349. Epub 2022 Oct 18.


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 (PGE2) or lipopolysaccharide (LPS)+interferon gamma (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, although directional inconsistency 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 models of microglia and show that only LPS provokes a transcriptional response along this axis in mouse microglia and LPS+IFN-γ in human iPSC-microglia. This article has an associated First Person interview with the first author of the paper.

Keywords: ATPγS; Alzheimer's disease; IFN-γ; LPS; PGE2; iPSC-microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Humans
  • Interferon-gamma / metabolism
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Microglia* / pathology
  • Transcriptome / genetics


  • Lipopolysaccharides
  • Interferon-gamma
  • Dinoprostone