Exploring the molecular interactions between cadmium and glycogen synthase kinase-3β in Alzheimer’s disease and their implications for neurodegeneration and therapeutic strategies

Abstract

Background: Alzheimer's Disease (AD) is a leading cause of dementia, characterized by neurodegeneration associated with the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins. Glycogen Synthase Kinase-3β (GSK3β) plays a critical role in these processes. Hypothesis: This study explores cadmium’s interaction with GSK3β, positing that cadmium-induced activation of GSK3β exacerbates neurodegeneration in AD. Materials and Methods: We employed bioinformatics tools for molecular docking analyses of cadmium acetate and GSK3β, utilizing structures from the Protein Data Bank. Binding affinities were assessed across multiple binding modes, with interactions analyzed using Discovery Studio and PyRx software. Results: Cadmium exhibited strong binding affinities to GSK3β, with the most favorable binding observed in Mode 1 (-3.4 kcal/mol). Interaction analysis revealed significant involvement of key residues (e.g., Arg223, Ser215), highlighting various bonding interactions, including hydrogen bonds and van der Waals forces. Conclusion: The findings indicate that cadmium binding may disrupt normal GSK3β function, potentially enhancing tau hyperphosphorylation and amyloid-beta accumulation, contributing to AD pathophysiology. This research underscores cadmium’s role as a neurotoxin in AD and suggests targeted therapeutic strategies to mitigate its effects on GSK3β, offering avenues for novel interventions in neurodegenerative diseases.