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P1‐078: BIN1 REGULATES BACE1 TRAFFICKING AND AB PRODUCTION
Author(s) -
Miyagawa Toji,
Morohashi Yuichi,
Ojima Ryota,
Tsuji Shoji,
Iwatsubo Takeshi,
Tomita Taisuke
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.314
Subject(s) - microbiology and biotechnology , endosome , intracellular , amyloid precursor protein secretase , subcellular localization , biology , amyloid beta , amyloid precursor protein , amyloid (mycology) , alzheimer's disease , biochemistry , cytoplasm , disease , medicine , peptide , botany
the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Ab production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Ab levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor kappa B (NF-kB) positively regulates BACE1 transcription. NF-kB 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 Ab 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. Methods: Human neuroblastoma SH-SY5Y cells were grown in Dulbecco’s modified Eagle’s medium:Ham’s F12 with Glutamax (1:1; v/v), 10% fetal bovine serum, and 1% antibiotic/antimycotic mix. Cells were maintained at 37 C in a saturated humidity atmosphere containing 95% air and 5% CO 2. After having reached 80% confluence, cells were incubated with vehicle (control), 10nM leptin, 400mM Sirtinol, and 10nM leptin + 400mM Sirtinol, for 24h at 37 C in cell medium. Results: Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-kB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-kB mediated transcription of BACE1 and consequently reduces Amyloid-b genesis.Conclusions:Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-b production and may help design potential therapeutic interventions.