Work

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

Year: 2026

Type: article

Abstract: 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. In Alzheimer’s disease (AD), uPAR has been implicated in both neuroinflammation and cellular senescence. However, it remains unclear to what extent uPAR is expressed across AD mouse models and how immune status influences cellular senescence in the brains of these mice. In this work, we investigated the time course and regional distribution of uPAR expression in mouse models of AD pathology in mice with intact or disrupted adaptive immunity. Brain tissue sections from immunodeficient Rag2/Il2rg-/- (Rag), and crossbred Rag2/Il2rg-/--5xFAD (Rag-5xFAD) as well as immunocompetent C57/BL6 (WT) and 5xFAD mice were immunostained against uPAR. The intensity and distribution of uPAR expression was evaluated in the primary motor cortex (M1), striatum, CA1, dentate gyrus (DG), subiculum, and thalamus. 5xFAD mice consistently exhibited greater uPAR-immunoreactivity than Rag and WT mice, as early as 4 months in Rag-5xFAD mice, and most notably at 6 months independent of immune condition. Triple-labeled immunofluorescence of the Aβ plaque marker methoxy X04, microglia marker Iba1, and the neuronal marker NeuN revealed overlap in Iba1 and uPAR expression, specifically surrounding Aβ plaques. Analysis of transcriptional changes was conducted using bulk-tissue RNA-sequencing in Rag-5xFAD mice, which revealed an upregulation in senescence and disease associated microglia (DAM) genes. These findings suggest uPAR regulation is a response of brain-resident cells, independent of peripheral adaptive immune signaling, ultimately contributing to AD pathogenesis.

Source: Brain Research

DOI: 10.1016/j.brainres.2026.150364