Prior studies have demonstrated a closed association between brain insulin resistance and Alzheimer’s disease (AD), while selenium supplementation was shown to improve insulin homeostasis in AD patients and to exert neuroprotective effects in a mouse model of AD. But the mechanisms underlying the neuroprotective actions of selenium remain incompletely understood. In this study we performed a label-free LC-MS/MS quantitative proteomics approach to analyze differentially expressed proteins (DEPs) in the hippocampus and cerebral cortex of APP/PS1 mice following 2 months of treatment with sodium selenate.