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Introduction: The mechanisms of vascular cognitive impairment (VCI) are poorly understood. We previously demonstrated increased expression and activity of soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem VCI. sEH is a key enzyme in the inactivation of endogenous lipid signaling mediators, epoxyeicosatrienoic acids (EETs), known to have vasodilator and anti-inflammatory properties.Hypothesis: Upregulation of endothelial sEH impairs cognition, by mechanisms involving reduced cerebral blood flow (CBF) and enhanced inflammation.Methods: Mice constitutively expressing human sEH in endothelium (Tie2-hsEH) and wild-type (WT) underwent unilateral common carotid artery occlusion (UCCAO) or sham surgery, then analyzed 4 months later for cognitive performance using the Morris water maze (MWM), CBF by perfusion MRI, immune cell profiling in brain, blood and spleen using fluorescence-activated cell sorting (FACS) and immunohistochemistry (IHC). Additionally, immune profiling was performed on WT mice 28 days following surgery, with and without pretreatment with immune modulator DRa1-hMOG-35-55 (HLA-DR a1 moiety linked to human MOG-35-55 peptide).Results: Tie2-hsEH mice showed impaired spatial memory retention in the MWM. No differences were observed in CBF between genotypes. IHC demonstrated a higher density of CD45-positive cells in Tie2-hsEH brain compared to WT. FACS analysis revealed a higher frequency of CD11b+CD45hi cells in Tie2-hsEH vs. WT mice. Furthermore, these cells express higher levels of CD74, the receptor for macrophage migration inhibitory factor (MIF). Similarly, following UCCAO, the frequency of antigen-presenting dendritic cells and CD74 expression on CD11b+CD45hi cells were increased in brain, but reduced in spleen and blood compared to naïve mice; both changes were reversed by treatment with DRa1-MOG-35-55, resulting in a decreased frequency and activation state of these cells.Conclusions: Our data suggest that infiltration of monocyte-derived macrophages may contribute to cognitive impairment in VCI. Our findings suggest that CD74 expression could serve as a biomarker for VCI, and that DRa1-MOG-35-55 may be effective in treating VCI.