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 CB 2 R-OX 1 R complex expression, while OX 1 R antagonism potentiates the neuroprotective effects of CB 2 R. Specifically, pretreatment with the OX 1 R antagonist has been shown to strongly potentiate CB 2 R signaling in the cAMP pathway. Furthermore, the blockade of OX 1 R can also abolish the detrimental effects of OX 1 R overactivation in AD. In this sense, CB 2 R-OX 1 R becomes a new potential therapeutic target to combat AD.