Selenium speciation drives differential neuroprotection by Se-enriched plant proteins against neuroinflammation

Selenium (Se)-containing compounds have emerged as promising neuroprotective nutrients. However, the effects of Se-enriched proteins with different Se species on neuroinflammation remain poorly understood. In addition, it remains unclear whether these effects are primarily attributable to Se or the protein matrix. This study aims to evaluate Se-enriched proteins with different Se species as neuroprotective nutraceutical candidates in an LPS-induced mouse model of neuroinflammation. Behavioral analyses showed that all three Se-enriched proteins alleviated LPS-induced cognitive impairment, with SeCys₂-enriched protein (Se-CVP) and SeMet-enriched protein (Se-SBP) providing better protection than Se(VI)-enriched protein (Se-CBP). Furthermore, Se-CVP enhanced hepatic Se accumulation, which was accompanied by a significant increase in plasma SEPP1 levels (p < 0.05). At the same Se concentration, Se-CVP also significantly inhibited glial activation compared with the model group, as evidenced by reductions of 43.3% and 53.9% in GFAP and IBA-1 fluorescence intensities, respectively. In contrast, Se-SBP showed a stronger effect on alleviating brain oxidative stress and significantly reduced Aβ_1-42 accumulation by 69.2%. These findings suggest that Se-enriched proteins with different Se species exert neuroprotective effects through distinct mechanisms. In LPS-stimulated BV-2 cells, Se-enriched protein digests exhibited stronger anti-neuroinflammatory activity than their low-Se counterparts at an equivalent protein concentration. Correlation analysis further revealed that the neuroprotective effect of Se-enriched proteins was more strongly associated with Se speciation than with the protein matrix, indicating that Se species play a dominant role in the observed effects. Overall, this study highlights the critical role of Se speciation in the neuroprotective effects of Se-enriched proteins against neuroinflammation.