Neuroprotective effects of G9a inhibition and cannabinoid receptor activation in Alzheimer's disease through a pharmacological approach

Epigenetic alterations are key contributors to Alzheimer's disease (AD), driving age-related cognitive decline. This study explores the combined neuroprotective effects of G9a histone methyltransferase inhibition (via UNC0642) and cannabinoid receptor activation (CB1R: ACEA; CB2R: JWH133) in AD models. We used HEK-293T cells and hippocampal neurons to demonstrate that G9a inhibition selectively enhances CB1R-mediated ERK/cAMP signaling. In SAMP8 mice (sporadic AD model), we evaluated the effects of pharmacological inhibition of G9a (UNC0642), combined with CB₁R agonism (ACEA) and/or CB₂R agonism (JWH133), on cognitive recovery, neuronal morphology, and neuroinflammation. Our results demonstrated that SAMP8 mice treated with UNC0642 and ACEA exhibited significant recovery in short-term memory, as assessed by the Novel Object Recognition Test (NORT), and complete recovery of spatial memory in the Object Location Test (OLT). These improvements were accompanied by enhanced neuronal morphology (increased dendritic length and density) and reduced neuroinflammation markers, suggesting a synergistic effect of G9a inhibition and CB₁R activation. Importantly, JWH133 treatment, both alone and in combination with UNC0642, resulted in a pronounced reduction of neuroinflammatory markers (Trem2, Cd33, iNOS) and a significant restoration of dendritic spine density and branching length, with the dual treatment showing the most robust effects. JWH133 alone produced moderate cognitive improvement, but its combination with G9a inhibition led to outcomes comparable to those of control animals. Thus, the results underscore G9a inhibition's potential to amplify cannabinoid receptor-mediated neuroprotection while mitigating psychoactive risks, offering a promising multi-target approach for neurodegenerative diseases.