Sodium selenite inhibits gamma-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 endogenous gamma-secretase activity. Consistently, the gamma-secretase-mediated production of amyloid-beta (Abeta) was dramatically attenuated by sodium selenite in a temporal manner. To substantiate the functional role of ERK MAPK 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 Abeta production, supporting that selenium compounds could represent a novel class of nutrient supplements to slow down the progression of Alzheimer's disease.
Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Ying-Tsen
YT
Tung
Wen-Ming
WM
Hsu
Bo-Jeng
BJ
Wang
Shin-Ying
SY
Wu
Chen-Tung
CT
Yen
Ming-Kuan
MK
Hu
Yung-Feng
YF
Liao
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018038:Sodium Selenite / Q000494:pharmacology*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; D018038:Sodium Selenite