Selenomethionine Attenuates the Amyloid-β Level by Both Inhibiting Amyloid-β Production and Modulating Autophagy in Neuron-2a/AβPPswe Cells

Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-beta (A beta) has been recognized as the major cause of AD. Inhibiting A beta production and/or enhancing the clearance of A beta to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-beta (A beta) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the A beta levels in Neuron-2a/A beta PPswe (N2asw) cells, and the anti-amyloid effect of Se-Metwas attributed to its ability to inhibit A beta generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted A beta clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD.