title: Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway.
abstract: The aspartyl protease β-site AβPP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in Aβ production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Aβ production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Aβ levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor - kappa B (NF-κB) positively regulates BACE1 transcription. NF-κB 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 Aβ 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-κB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-κB-mediated transcription of BACE1 and consequently reduces Amyloid-β genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-β production and may help design potential therapeutic interventions.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
authors.forename: Gurdeep
authors.initials: G
authors.lastname: Marwarha
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
authors.forename: Shaneabbas
authors.initials: S
authors.lastname: Raza
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Meiers
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA. Electronic address: othman.ghribi@med.und.edu.
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D020738:Leptin; D016328:NF-kappa B; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Alzheimer's Disease; Amyloid-β; BACE-1; Leptin; NF-κB; SIRT1