NRF2 activation by 6-MSITC increases the generation of neuroprotective, soluble α amyloid precursor protein by inducing the metalloprotease gene ADAM17.

Abstract

Better knowledge of the molecular actors governing sequential amyloid precursor protein (APP) proteolysis is crucial to endorse novel therapies aimed to delay Alzheimer's disease (AD) progression. ADAM17 (A Disintegrin and Metalloproteinase 17) is a type-I transmembrane protease involved in the non-amyloidogenic processing of APP that contributes to the maintenance of synaptic functions. In this work, we analyzed the 5'-flanking region and first intron of ADAM17 gene employing an in silico analysis. This strategy evidenced two regions which concentrate the binding sites of diverse transcription factor-families, including members of the b-ZIP small MAF, NRF2 and BACH1 proteins. Then, we found that the natural isothiocyanate 6-MSITC (6 methylsulfinyl hexyl isothiocyanate) increased both mRNA and protein levels of ADAM17 in an NRF2-dependent manner. In line, SH-SY5Y neurons released higher levels of the soluble APPα peptide as a result of ADAM17 activation. Overall, our study identifies inducible expression of ADAM17, and consequently protease activity, by NRF2.