La segnalazione endocannabinoide nella malattia di Alzheimer: un nuovo bersaglio per la comprensione dei meccanismi della patologia e del potenziale ruolo terapeutico dei lipidi bioattivi

Alzheimer’s Disease (AD) is a leading neurodegenerative disorder and the primary cause of dementia among the elderly (Citron, 2010). Chronic neuroinflammation has emerged as a critical factor in neuronal loss in AD, with microglial cells playing a central role. This exacerbated pro-inflammatory environment may be influenced by microglial senescence, characterized by a persistent activation state and the adoption of a senescence-associated secretory phenotype (SASP), which amplifies neuroinflammation and oxidative stress, ultimately contributing to neuronal damage and cognitive decline (Streit et al., 2014; Y. Wang et al., 2022). In this scenario, the endocannabinoid system (ECS) has gained attention as a critical modulator of immune and inflammatory responses, influencing microglial function and cellular senescence (Muccioli et al., 2007; Stella, 2009). Microglia express receptors and enzymes associated with the ECS, enabling the production of bioactive lipids like N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), which play key roles in promoting anti-inflammatory phenotypes during early neuropathology (Walter et al., 2003). This study aims to investigate the role of the ECS in the processes of immunosenescence associated with AD. Neonatal microglia were isolated from both wild-type and Tg2576 mice—an AD-like model that overexpresses Aβ peptides—and exposed to chronic lipopolysaccharide (LPS) stimulation to model immunosenescence. Our results revealed that embryonic Aβ exposure in Tg2576 microglia alone was insufficient to induce a senescent phenotype. Instead, the combination of in vivo Aβ exposure during embryogenesis and in vitro LPS treatment was required to drive senescence, characterized by elevated β-galactosidase activity and increased expression of senescence markers, including p16, CD11c, TREM2, and lipofuscin (González-Gualda et al., 2021). Our research highlights the significant potential of fatty acid amide hydrolase (FAAH) inhibition in reversing microglial senescence. Treatment with 3′-carbamoyl[1,1′-biphenyl]-3-yl cyclohexyl-carbamate (URB597), a selective FAAH inhibitor, reduced key senescence markers and modulated NF-κB activity, with enhanced AEA signaling critically suppressing NF-κB activation, a core component of the SASP (Wang et al, 2022). Furthermore, while elevated 2-AG levels in Tg2576 microglia were identified as a maladaptive response to chronic Aβ exposure, the findings indicate that this dysregulation, rather than 2-AG itself, exacerbates the pro-inflammatory and senescence-like phenotypes. In wild-type microglia, chronic exposure to 2-AG in combination with LPS did not induce a senescent phenotype, highlighting that the pathological effects are contingent upon the endogenous enzymatic imbalance in 2-AG synthesis and degradation. Cyclooxygenase-2 (COX-2) inhibition mitigated LPS-induced senescence markers, further supporting that 2-AG degradation through this pathway may drives microglial dysfunction in the context of AD.