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

Gurdeep Marwarha, Shaneabbas Raza, Craig Meiers, Ghribi Othman

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1587-1595
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number9
DOIs
StatePublished - Jan 1 2014

Fingerprint

Leptin
Amyloid
NF-kappa B
Aspartic Acid Proteases
Adipokines
Acetylation
Neuroblastoma
Transcriptional Activation
Signal Transduction
Alzheimer Disease
Transcription Factors
Peptides
Enzymes

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • BACE-1
  • Leptin
  • NF-κB
  • SIRT1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway. / Marwarha, Gurdeep; Raza, Shaneabbas; Meiers, Craig; Othman, Ghribi.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 9, 01.01.2014, p. 1587-1595.

Research output: Contribution to journalArticle

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