Stress-Responsive Transcriptomic Signatures in Human iPSC-Derived Microglia Reveal Links to Alzheimer’s Disease Risk Genes

Cellular stress responses are essential for maintaining homeostasis in the face of environmental or internal challenges. In the central nervous system, microglia serve as key stress sensors and immune responders, shaping neuroinflammatory processes and disease progression. However, the molecular programs engaged by distinct stressors and their impact on microglial viability remain incompletely understood.

In this study, we used human induced pluripotent stem cell-derived microglia-like cells to investigate stress responses to amyloid beta (Aβ), a chronic Alzheimer’s disease–related stressor, and lipopolysaccharide (LPS), a classical acute inflammatory stimulus. Using single-cell RNA sequencing, we mapped the transcriptional programs activated by each condition and benchmarked these states against reference microglial datasets from mouse and human brains. In parallel, we performed a pooled CRISPR interference screen targeting Alzheimer’s disease-associated microglial genes to identify genetic determinants of microglial survival.

We found that Aβ and LPS elicit partially overlapping but distinct transcriptional responses. Aβ induced more focused and disease-associated gene expression changes, while LPS triggered broad inflammatory activation and stronger cell death signatures. A subset of genes activated by stress overlapped with Alzheimer’s disease risk genes and with hits from the survival screen, suggesting that disease-associated microglial genes may contribute to stress adaptation and cellular fitness.

These results demonstrate that iPSC-derived microglia-like cells can recapitulate in vivo–like stress-responsive states and offer a tractable platform to investigate genetic and environmental influences on microglial behavior. Together, our findings reveal transcriptional programs that link stress sensing, survival regulation, and Alzheimer’s disease–associated gene networks, providing a foundation for future efforts to enhance microglial resilience in neurodegenerative disease contexts.