NPD1 Enhances Autophagy and Reduces Hyperphosphorylated Tau and Amyloid-beta(42) by Inhibiting GSK3 beta Activation in N2a/APP695swe Cells

Background: The most prevalent kind of dementia, Alzheimer's disease (AD), is a neurodegenerative disease. Previous research has shown that glycogen synthase kinase-3 beta (GSK-3 beta) is involved in the etiology and progression of AD, including amyloid-beta (A beta), phosphorylated tau, and mitochondrial dysfunction. NPD1 has been shown to serve a neuroprotective function in AD, although the mechanism is unclear. Objective: The effects of NPD1 on A beta expression levels, tau protein phosphorylation, apoptosis ratio, autophagy activity, and GSK-3 beta activity in N2a/APP695swe cells (AD cell model) were studied, as well as the mechanism behind such effects. Methods: N2a/APP695swe cells were treated with NPD1, SB216763, or wortmannin as an AD cell model. The associated proteins of hyperphosphorylated tau and autophagy, as well as the activation of GSK3 beta, were detected using western blot and RT-PCR. Flow cytometry was utilized to analyze apoptosis and ELISA was employed to observe A beta(42). Images of autophagy in cells are captured using transmission electron microscopy. Results: In N2a/APP695swe cells, NPD1 decreased A beta(42) and hyperphosphorylated tau while suppressing cell death. NPD1 also promoted autophagy while suppressing GSK-3 beta activation in N2a/APP695swe cells. The outcome of inhibiting GSK-3 beta is comparable to that of NPD1 therapy. However, after activating GSK-3 beta, the opposite experimental results were achieved. Conclusion: NPD1 might minimize cell apoptosis, downregulate A beta expression, control tau hyperphosphorylation, and enhance autophagy activity in AD cell models to promote neuronal survival. NPD1's neuroprotective effects may be mediated via decreasing GSK-3 beta.