uPAR exhibits age- and region-dependent expression in the brains of mice with Alzheimer's disease-like pathology.

The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell surface protein that regulates leukocyte adhesion, migration, and activation, thereby contributing to inflammation and tissue remodeling. However, its role in Alzheimer's disease (AD), particularly in relation to glial dysfunction, remains poorly defined. Here, we investigated the temporal and spatial regulation of uPAR expression across AD mouse models with intact or deficient adaptive immunity. Using immunohistochemistry, we assessed uPAR expression in Rag2/Il2rg-/- (Rag), Rag2/Il2rg-/--5xFAD (Rag-5xFAD), C57BL/6 (WT), and 5xFAD mice across multiple brain regions. uPAR expression increased with age and was significantly elevated in 5xFAD mice, with robust upregulation evident by 6 months irrespective of immune status. Immunofluorescence revealed that uPAR localized predominantly to Iba1+ microglia clustered around Aβ plaques, with limited neuronal expression. Bulk RNA sequencing of Rag-5xFAD brain tissue demonstrated enrichment of disease-associated microglia (DAM) and senescence-related transcriptional programs. These findings indicate that uPAR marks a subset of plaque-associated glial cells undergoing functional and transcriptional remodeling in AD, independent of peripheral adaptive immune signaling. Collectively, our results identify uPAR as a marker of dysfunctional, DAM-like microglia and implicate it in senescence-associated neuroinflammatory pathways. This work provides a framework for future studies targeting uPAR-expressing glial populations as a potential therapeutic strategy in AD.