Sodium selenite inhibits γ-secretase activity through activation of ERK

Previous studies have demonstrated that the ERK MAPK acts as a negative regulator of γ-secretase. Here, we demonstrate that the activation of ERK MAPK pathway by sodium selenite can inhibit endogenous γ-secretase activity. Consistently, the γ-secretase-mediated production of amyloid-β (Aβ) was dramatically attenuated by sodium selenite in a temporal manner. To substantiate the functional role of ERK MAPK in the regulation of γ-secretase, we demonstrate that cells transfected with the wild-type MEK1 and a constitutively active mutant of MEK1 also displayed a significant attenuation of γ-secretase activity. The active purified ERK1/2 can significantly reduce the γ-secretase-mediated processing of C99, possibly through inducing alterations in the phosphorylation of both nicastrin and presenilin-1. Together, our data suggest that the selenite-elicited ERK activation could effectively reduce Aβ production, supporting that selenium compounds could represent a novel class of nutrient supplements to slow down the progression of Alzheimer's disease.