Comprehensive single-cell transcriptomic atlas of microglia in Alzheimer's disease mouse models

Microglia are central mediators of neuroinflammation in Alzheimer's disease (AD), yet conserved microglial states and activation trajectories across AD mouse models remain incompletely defined. Here, we constructed a comprehensive Mouse Microglia Atlas (MoMicA) to resolve conserved subtypes, delineate dynamic trajectories, and identify key regulators associated with AD pathology. We integrated ten single-cell and single-nucleus RNA-sequencing datasets from major AD mouse models, yielding 84,764 microglia for harmonized clustering, co-expression network analysis, and pseudotime inference, complemented by immune staining. Across models, AD was characterized by contraction of homeostatic microglia and marked expansion of DAM. MoMicA further delineated refined homeostatic and disease-associated subpopulations, including different homeostatic microglia subclusters and a stepwise progression from homeostatic microglia through activated response and pre-disease-associated states to disease-associated microglia. Network analysis highlighted lipid metabolism and inflammation as dominant AD-related programs and identified Fabp5 as a central hub gene within a DAM-associated lipid module. Multiplex immunofluorescence confirmed that Fabp5 is induced in Clec7a-positive DAM around amyloid plaques in two amyloidosis models. MoMicA therefore provides a valuable resource for dissecting the mechanistic roles of microglia in the onset and progression of AD.