Exploring Cellular Heterogeneity: Single-Cell and Spatial Transcriptomics of Alzheimer Disease Brains and iPSC-Derived Microglia

Background Substantial evidence has established the critical role of microglia, the brain's resident immune cells, in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit diverse transcriptional states in response to neuroinflammatory stimuli, and understanding these states is crucial for elucidating the underlying mechanisms of AD. Methods In this work, we integrated single-cell and spatially resolved transcriptomics data from multiple cohorts and brain regions, including microglia from experimental and human brains. Results This comprehensive atlas revealed a great heterogeneity of microglial states, with a significant enrichment of specific states, including activated microglia, in AD brains compared to controls. Further integration of spatial transcriptomics and immunohistochemistry showed that activated microglia are predominantly located in the external cortical layers near amyloid plaques, while homeostatic microglia are more prevalent in the internal cortical layers and further away from the plaques. These spatial patterns were further validated using P2RY12 immunostaining, which confirmed the reliability of the transcriptomic data. Conclusion By integrating single-cell and spatial transcriptomics, we have provided a detailed atlas of microglial diversity, revealing the regional and pathological specificity of microglial states.