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Updated: Aug 25, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Lipopolysaccharide distinctively alters human microglia transcriptomes to resemble microglia from Alzheimer's disease
Jimena Monzón-Sandoval1, Elena Burlacu2, Devika Agarwal3,4
1UK Dementia Research Institute, Cardiff University, Cardiff CF24 4HQ, UK.
Abstract:
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.
Insights
Induced pluripotent stem cell-derived microglia (iPSC-microglia) show overlapping gene expression changes with Alzheimer's disease (AD) patients, but responses to immune stimuli vary. This study clarifies iPSC-microglia responses for better AD modeling.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) pathogenesis involves neuroimmunity, with microglia playing a key role.
- Induced pluripotent stem cell-derived microglia (iPSC-microglia) are valuable models for studying AD.
- The relevance of historical immune stimuli in iPSC-microglia models for AD requires clarification.
Purpose of the Study:
- To compare the effects of various immune stimuli on iPSC-microglia over time.
- To assess the relevance of these responses to Alzheimer's disease.
- To identify conserved transcriptomic changes in microglia relevant to AD.
Main Methods:
- Single-cell RNA sequencing was used to analyze iPSC-microglia transcriptional responses.
- Cells were stimulated with prostaglandin E2 (PGE2), lipopolysaccharide (LPS)+interferon gamma (IFN-γ), and ATPγS, alone or in combination.
- Transcriptional data were compared across conditions and with human AD microglia and AD mouse models.
Main Results:
- A shared core transcriptional response was observed between iPSC-microglia stimulated with ATPγS and LPS+IFN-γ.
- Significant overlap in gene expression changes was found between iPSC-microglia and human AD microglia, despite directional inconsistencies.
- A common transcriptomic change axis was identified in AD mouse models, with LPS and LPS+IFN-γ selectively activating this axis in mouse and human iPSC-microglia, respectively.
Conclusions:
- iPSC-microglia exhibit convergent transcriptional responses to certain immune stimuli.
- While iPSC-microglia share gene expression overlap with AD patient microglia, specific stimuli differentially activate conserved pathways.
- This research provides insights into optimizing iPSC-microglia for modeling AD neuroimmunity and identifying AD-relevant microglial responses.
