Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway

The aspartyl protease beta-site A beta PP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in A beta production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce A beta production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in A beta levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor - kappa B (NF-kappa B) positively regulates BACE1 transcription. NF-kappa B activity is tightly regulated by the mammalian sirtuin SIRT1. Multiple studies have cogently evinced that leptin activates the metabolic master regulator SIRT1. In this study, we determined the extent to which SIRT1 expression and activity regulate the leptin-induced attenuation in BACE1 expression and A beta levels in cultured human neuroblastoma SH-SY5Y cells. This study also elucidated and delineated the signal transduction pathways involved in the leptin induced mitigation in BACE1 expression. Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-kappa B by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-kappa B-mediated transcription of BACE1 and consequently reduces Amyloid-beta genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-P production and may help design potential therapeutic interventions. (C) 2014 Elsevier B.V. All rights reserved.