Endocannabinoid regulation of microglia–astrocyte crosstalk in Alzheimer’s disease

Neuroinflammation is a hallmark of aging and neurodegenerative disorders, including Alzheimer’s disease (AD). In the healthy brain, microglia and astrocytes support tissue repair, synaptic remodeling, and clearance of toxic aggregates, aided by anti-inflammatory cytokines that maintain homeostasis. During chronic neurodegeneration, persistent stimuli, such as amyloid β plaques, drive sustained microglial activation, leading to excessive pro-inflammatory cytokine release, synaptic dysfunction, and neuronal loss. The endocannabinoid system (ECS), comprising cannabinoid receptors 1 and 2 (CB1R and CB2R), the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, plays a critical role in regulating neuroimmune balance. ECS signaling modulates microglial and astrocytic activity, promoting neuroprotection and resolution of inflammation. Given the limited effectiveness of current AD therapies, targeting ECS pathways offers a strategy to mitigate neuroinflammation and improve cognitive outcomes as well as manage neuropsychiatric symptoms. This narrative review integrates mechanistic, translational, and clinical evidence published between 2002 and 2026 to evaluate ECS modulation as a therapeutic approach in AD. The preclinical evidence supports the potential of the ECS in mitigating neuroinflammation. However, these findings have not yet been clinically validated, and a significant translational gap remains between preclinical and clinical research, partly due to differences in cellular and molecular mechanisms between animal models and humans. Further research is warranted to validate these findings and establish the therapeutic relevance of ECS modulation in clinical settings.