ERK activation induced by selenium treatment significantly downregulates β/γ-secretase activity and Tau phosphorylation in the transgenic rat overexpressing human selenoprotein M

Abstract

Selenium reportedly contribute to the modulation process of protein phosphorylation to regulate various cellular functions including growth, differentiation, proliferation and development. The aim of this study was to investigate whether selenium and Selenoprotein M (SelM) affects the mechanism of Alzheimer's disease. To achieve this, we determined the change of the MAPK pathway, secretase activity, and Tau phosphorylation in the transgenic rat overexpressing human selenoprotein M. Based on these results, we concluded that, i) CMV/GFP-hSelM Tg rats showed a high activity level of antioxidant enzyme in the brain tissues, ii) in response to selenium treatment, the ERK signaling pathway was significantly increased in the Tg rats, but did not change in the wild-type rats, iii) the activation of ERK pathway by selenium treatment and SelM overexpression induced the inhibition of the β/γ-secretase activity related to the protection of Aβ-42 production, iv) the activation of the ERK pathway by selenium treatment and SelM overexpression inhibited the phosphorylation in several site of Tau protein. Therefore, these results provide strong evidence that selenium treatment and SelM activate the ERK pathway to attenuate β/γ-secretase-mediated proteolysis and Tau phosphorylation to protect brain function.;Selenium은 단백질의 인산화 과정에 관여함으로써 다양한 세포내에서 성장, 분화, 증식, 발달을 조절한다. 본 연구에서는 selenium과 SelM의 Alzheimer's disease에 미치는 영향을 알아보고자 하였다. 이를 위해, selenoprotein M을 과발현 시킨 형질전환 랫드에서 selenium 처리에 따른 MAPK pathway, secretase acivity와 tau phosphorylation의 변화를 관찰하였다. 그 결과 다음과 같은 현상을 관찰하였다. 1) CMV/GFP-hselM 형질전환 랫드의 뇌에서 항산화효소 level이 높게 나타났다. 2) selenium 처리 후 ERK 신호전달 pathway는 형질전환 랫드에서 유의적으로 증가하였으나 비형질전환 랫드에서는 변화가 없었다. 3) selenium 처리와 selM의 과발현에 의한 ERK pathway 활성은 Aβ42 생성에 관여하는 β/r-secretase activity를 억제함을 확인하였다. 4) selenium 처리와 selM의 과발현에 의한 ERK pathway 활성은 Tau 단백질의 인산화를 억제함을 확인 하였다. 이러한 결과 selenium 처리와 SelM 과발현은 뇌에서 ERK pathway가 활성을 유도함으로써 β/r-secretase와 tau 인산화를 감소시킨다는 것을 제시하고 있다.