Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control

Abstract

Alzheimers disease has traditionally been associated with amyloid-{beta} plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoimmune hypothesis of Alzheimers disease suggests chronic inflammation and immune dysfunction contribute to neuronal damage, making modulation of immune responses a promising therapeutic strategy for the disease. Cannabidiol, a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study explores how cannabidiol influences the Indoleamine 2,3-dioxygenase (IDO) and cyclic GMP-AMP synthase (cGAS) pathway, a key regulator of neuroinflammation in Alzheimers disease. Using the 5XFAD transgenic mouse model of Alzheimers disease, we administered cannabidiol via inhalation. We assessed immune markers, including Indoleamine 2,3-dioxygenase and cyclic GMP-AMP synthase, through flow cytometry, immunofluorescence staining, and gene expression analysis. Cytokine levels and neuroinflammatory responses were evaluated, and protein-protein interactions within the Indoleamine 2,3-dioxygenase/cyclic GMP-AMP synthase pathway were analyzed using the STRING database. Cannabidiol treatment significantly reduced Indoleamine 2,3-dioxygenase and cyclic GMP-AMP synthase expression, correlating with lower levels of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha, Interleukin-1 beta, and Interferon-gamma. Bioinformatics analysis identified potential interactions between cannabidiol and immune targets such as Protein Kinase B (AKT1), Transient Receptor Potential Vanilloid 1, and G-protein coupled receptor 55, suggesting a multi-targeted therapeutic effect. These findings support cannabidiol as a potential monotherapy or adjunctive treatment for Alzheimers disease, targeting neuroinflammatory pathways, particularly the Indoleamine 2,3-dioxygenase/cyclic GMP-AMP synthase axis. Further studies are needed to explore its full therapeutic potential.