Targeting GSK3β with a Synthetic Small Molecule Rescues Neurotoxicity in a Cellular Model of Alzheimer's Disease

The neuropathological presentation of Alzheimer's disease (AD) constitutes amyloid-β plaques and Tau tangles. Activation of GSK3β contributes to neurodegeneration by directly promoting tau hyperphosphorylation and amyloid-β formation. An earlier study also reported the overexpression of GSK3β in AD patients. This work designed and synthesized tetrapeptides [VYS(p)W, AKS(p)F, and DKS(p)F] containing a phosphate group attached to the serine residue, which mimicked the primed phosphorylated substrate of GSK3β. According to the network study, through interaction with various proteins and alteration of the molecular pathway of AD, the DKS(p)F peptide may exhibit a wide range of effects. The binding study of the peptide was performed by label-free surface plasmon resonance. The rescue effect of peptide on neurotoxicity was measured by MTT assay in SH-SY5Y cells. The peptide DKS(p)F was found to have the best docking score and binding energy with GSK3β. The low dissociation constant, (9.58 × 10^-8 M), indicates strongest binding capacity with GSK3β. The reduction in neurotoxicity of SH-SY5Y cells was observed after treatment with DKS(p)F by suppressing the levels of amyloid-β, Tau, and p-Tau proteins. This peptide can be one of the promising molecules for ongoing efforts to develop therapeutic molecules for the neurodegenerative disorder of Alzheimer's disease.