Effect of Resveratrol on PI3K/Akt/GSK-3β Pathway and Metalloproteases in Differentiated and Aβ-Induced Alzheimer's Model Neuroblastoma Cells

Purpose To analyze the expressional changes in the PI3K/Akt/GSK-3β pathway and metalloprotease in the cellular AD model with the effect of antioxidant resveratrol. Methods We obtained neuron-like cells by a two-step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain-derived factor (BDNF) exposure. Then, the application of the Aβ25–35 protein (10 µM) to the cell culture mimicked the environmental toxicity observed in Alzheimer's disease. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, we analyzed with Real-Time PCR, the expressional changes in genes in the cellular AD model with the effect of resveratrol. Results Apoptosis data findings were decreased by 1.5-fold and 2.5-fold respectively by differentiated + RES and RES when compared to control but no significant difference was observed between resveratrol and AD model groups. Real-time PCR analysis results revealed PI3K (3.38-fold), AKT (3.95-fold), and RELN (1.99-fold) expressions were significantly higher (p < 0.001), and also GSK-3β, TAU, ADAMTS-4, ADAMTS-5, and TIMP-3 gene expression levels were significantly downregulated (2.53-, 1.79-, 2.85-, 4.09-, and 6.62- fold, respectively) in the differentiated + Aβ + RES groups compared to the differentiated + Aβ group (p < 0.001). Conclusion Resveratrol has inhibited GSK-3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.