Myeloperoxidase ablation ameliorates behavioral and inflammatory-related features in the 5XFAD mouse model of alzheimer's disease (AD)

Abstract

Background & Aim Myeloperoxidase (MPO) is a potent enzyme expressed mostly by neutrophils, that catalyzes the formation of reactive oxygen species (ROS), mainly hypochlorous acid. MPO is a primary mediator of neutrophils oxidative stress response and was shown to be essential for the formation of neutrophils extracellular traps (NETs). Upon secretion, MPO was also shown to attach to blood endothelial cells and promote their degradation, making it a therapeutic target in multiple clinical incidences, including neurodegenerative disorders. Here, we aimed to assess the role of neutrophil-derived MPO in 5XFAD model of AD. Methods, Results & Conclusion For that purpose, we subjected 5XFAD mice to myeloablative irradiation and bone marrow-repopulation from MPO Knock-out (KO) mice to form 'MPO KO-5XFAD' mice. MPO KO-5XFAD mice exhibited improvement in their risk assessment behavior, as measured by the 'Elevated plus maze/ test and the 'Open field' test, when compared to 5XFAD mice transplanted with WT cells (termed 'WT-5XFAD'). Remarkably, MPO KO-5XFAD mice also showed improved spatial recognition and learning, as was evident in the 'Y-maze' test, the 'Morris water maze' test and by 'Contextual fear conditioning' test. Hippocampal RNA expression analysis by QPCR indicated decreased expression of proinflammatory cytokines in MPO KO-5XFAD mice, along with decreased blood brain barrier damage and reduced expression of murine APOE. Together, these results indicate a substantial involvement of blood-derived oxidative damage in mouse model of AD, and assign MPO as a potential therapeutic target in AD.