ARGINASE-2 CONTRIBUTES TO AGE-ASSOCIATED COGNITIVE IMPAIRMENT AND ENDOTHELIAL ACTIVATION IN MICE

Brain aging is characterized by progressive cognitive decline and cellular dysfunction driven by complex molecular and vascular changes. Arginase-2 (Arg-II), a mitochondrial enzyme known to increase with age across multiple organs, has been implicated in aging-related pathologies. In this study, we investigated the role of Arg-II in brain aging. Using young (3-6 months) and aged (24-26 months) wildtype (WT) and Arg-II knockout (arg-ii^-/-) mice, we performed behavioral, histological and biochemical analyses. In the Y-maze test, aged WT mice exhibited reduced spontaneous alterations compared to their young counterparts, whereas aged arg-ii^-/- mice showed significantly improved performance relative to aged WT animals. Furthermore, aged WT mice displayed decreased protein expression of NMDAR and GluR-1 (AMPAR subunit) in the hippocampus, changes absent in aged arg-ii^-/- mice. Screening for inflammatory markers revealed increased endothelial ICAM1 expression in the hippocampus of aged WT but not arg-ii^-/- mice, suggesting Arg-II-dependent endothelial activation. To examine a putative role of endothelial Arg-II, we generated an endothelial cell specific Arg-II knockout mouse (arg-ii^fl/fl:Tie2Cre). These animals showed similar age-associated memory impairment and ICAM1 upregulation in the hippocampus as their control group, indicating that loss of endothelial Arg-II alone does not prevent age-related vascular inflammation and cognition decline. Collectively, our findings demonstrate that Arg-II promotes neuronal dysfunction and cognitive impairment independently of hippocampal endothelial Arg-II.