Cannabinoid and Orexigenic Systems Interplay as a New Focus of Research in Alzheimer's Disease

Alzheimer's disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep-wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB₂R-OX₁R complex expression, while OX₁R antagonism potentiates the neuroprotective effects of CB₂R. Specifically, pretreatment with the OX₁R antagonist has been shown to strongly potentiate CB₂R signaling in the cAMP pathway. Furthermore, the blockade of OX₁R can also abolish the detrimental effects of OX₁R overactivation in AD. In this sense, CB₂R-OX₁R becomes a new potential therapeutic target to combat AD.