Molecular Insights to the Wnt Signaling During Alzheimer's Disorder: a Potential Target for Therapeutic Interventions

In the adult brain, Wnt signaling is crucial for neurogenesis, and it also regulates neuronal development, neuronal maturation, neuronal differential, and proliferation. Impaired Wnt signaling pathways are associated with enhanced levels of amyloid-β, reduced β-catenin levels, and increased expression of GSK-3β enzyme, suggesting its direct association with the pathogenesis of Alzheimer's disorder (AD). These findings are consolidated by reports where activation of Wnt signaling by genetic factors and pharmacological intervention has improved the cognitive functions in animals and restored neurogenesis in the adult brain. Various natural and synthetic molecules have been identified that modulate Wnt signaling in the adult brain and promote neurogenesis and alleviate behavioral dysfunction. These molecules include lithium, valproic acid, ethosuximide, selenomethionine, curcumin, andrographolide, xanthoceraside, huperzine A, pyridostigmine, ginkgolide-B, ricinine, cannabidiol, and resveratrol. These molecules are associated with the DKK1 and GSK-3β inhibition and β-catenin stabilization along with their effects on neurogenesis, neuronal proliferation, and differentiation in the hippocampus through modulation of Wnt signaling and thereby could prove beneficial in the management of AD pathogenesis. Although modulation of the Wnt signaling seems to suggest to be promising in the management of AD, unfortunately, most of the literature available for the association of Wnt signaling and AD pathogenesis is either from preclinical studies or post-mortem brain. Therefore, it will be interesting to understand the role of Wnt signaling in AD patients, and a rigorous investigation could provide us with a better understanding of AD pathogenesis and the identification of novel targets for therapeutic interventions.