Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (A beta) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation. In AD, canonical Wingless-Int (Wnt)/beta-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor gamma (PPAR gamma) is increased. Downregulation of Wnt/beta-catenin, through activation of glycogen synthase kinase-3 beta (GSK-3 beta) by A beta, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, A beta-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3 beta, an inhibitor of Wnt pathway. CBD may also increase Wnt/beta-catenin by stimulation of PPAR gamma, inhibition of A beta and ubiquitination of amyloid precursor protein. CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPAR gamma, pro-inflammatory signaling and may be a potential new candidate for AD therapy.