Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer's disease.

Background and purpose Activation of type-2 Imidazoline receptors has been shown to exhibit neuroprotective properties including anti-apoptotic and anti-inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the Imidazoline-2 ligand BU224 in a model of amyloidosis. Experimental approach 6-month-old female transgenic 5XFAD and wild-type (WT) mice were treated intraperitoneally with 5 mg.kg-1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, ELISA and qPCR. Effects of BU224 on APP processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells. Key results BU224 treatment attenuated spatial and perirhinal cortex-dependent recognition memory deficits in 5XFAD mice. Fear conditioning testing revealed that BU224 also improved both associative learning and hippocampal- and amygdala-dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro-inflammatory cytokines IL-1β and TNFα, and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a 3-fold reduction in Aβ-induced functional changes in NMDA receptors. Conclusions and implications Our data indicate that sub-chronic treatment with BU224 improves memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.