THE CB<SUB>2</SUB>R-OX<SUB>2</SUB>R HETEROMER IN MICROGLIA: A PROMISING THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE

The endocannabinoid receptor CB₂ is mainly expressed in glial cells at the Central Nervous System level. Moreover its expression is further increased when these cells are activated under an inflammatory process. Conversely, CB₂R shows low expression levels in hippocampal neurons. In fact, many authors doubt about its neuronal expression. Among the pathologies that courses with an inflammation process, Alzheimer’s disease stands out. Alzheimer’s disease is also characterized by the alteration of the sleep-wake cycle, where the orexinergic system has a regulatory role. It appears that the OX₁R receptor activation favours beta-amyloid peptide accumulation due to the sleep disturbances. However, the role of the OX₂R receptor remains unclear.
In this study, we focused on evaluating the roles of CB₂R and OX₂R receptors in Alzheimer’s disease. Our results indicate that both receptors exert beneficial effects by reducing neuronal death and oxidative stress in primary cultures of activated microglia with LPS and IFN-γ and in 5xFAD mice model of AD. Furthermore, activation of the CB₂R receptor polarized microglia toward a neuroprotective M2 phenotype. These effects were even more potent when activated microglia were co-treated with the agonists of both receptors, leading to decreased ROS production, reduced microglial inflammation, and lower levels of cell death. These outcomes can be explained by the direct interaction between the two receptors, which results in a positive cross-talk phenomenon.
In conclusion, these findings present the CB₂R–OX₂R heteromer as a novel therapeutic target to combat inflammation and reduce the symptomatology of Alzheimer’s disease.