Sodium selenite inhibits γ-secretase activity through activation of ERK

Previous studies have demonstrated that the ERK MAPK acts as a negative regulator of gamma-secretase. Here, we demonstrate that the activation of ERK MAPK pathway by sodium selenite can inhibit enclogenous gamma-secretase activity. Consistently, the gamma-secretase-mediated production of amyloid-beta (A beta) was dramatically attenuated by sodium selenite in a temporal manner. To substantiate the functional role of ERK MAPI( in the regulation of gamma-secretase, we demonstrate that cells transfected with the wild-type MEK1 and a constitutively active mutant of MEK1 also displayed a significant attenuation of gamma-secretase activity. The active purified ERK1/2 can significantly reduce the gamma-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 AD production, supporting that selenium compounds could represent a novel class of nutrient supplements to slow down the progression of Alzheimer's disease. (C) 2008 Elsevier Ireland Ltd. All rights reserved.