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

Abstract

Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy.Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the Indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence, and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions. CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation. These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.Significance statement This study highlights the therapeutic potential of cannabidiol (CBD) in targeting neuroinflammation, a major driver of Alzheimer's disease (AD) progression. By modulating the IDO and cGAS pathways-critical regulators of CNS immune responses-CBD reduces pro-inflammatory cytokines and ameliorates immune dysfunction. These findings support the emerging autoinflammatory hypothesis of AD, which posits that chronic inflammation underlies neuronal damage. The IDO/cGAS signaling axis, located at the intersection of innate immunity and metabolic regulation, remains underexplored in AD and represents a key intervention point to disrupt neuroinflammatory loops. This study positions CBD as a promising mono- or adjunctive therapy and reinforces the need to consider multi-targeted strategies that address upstream immune mechanisms in neurodegenerative disease.