Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer's disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.