A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.

Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snRNA-seq) studies have identified multiple transcriptional states of microglia in human AD brain. However, the characteristics and potential functions of G protein-coupled receptors (GPCRs) across different states remain poorly systematized. This review systematically searched and reviewed snRNA-seq studies based on human brain tissue published between 2020 and 2025. By re-analyzing GPCR expression across these datasets, we focuses on characterizing the differential expression characteristics and potential functions of GPCRs in five key AD-related microglial states: disease-associated microglia, tau-associated microglia, inflammation-associated microglia, proliferation-associated microglia, and interferon-associated microglia. Furthermore, we cross-reference these findings with single-cell sequencing data from human induced pluripotent stem cell (hiPSC)-derived microglia to prioritize a conserved set of GPCRs of high interest. In summary, by integrating transcriptomic evidence from both post-mortem human brain and hiPSC models, this review not only refines the understanding of microglial heterogeneity in AD but also provides a set of candidate GPCR targets for subsequent validation and drug discovery efforts against AD.