Galangin-induced down-regulation of BACE1 by epigenetic mechanisms in SH-SY5Y cells. (21st May 2015)

• Record Type: Journal Article
• Authors: Zeng, H.; Huang, P.; Wang, X.; Wu, J.; Wu, M.; Huang, J.
• Is Part Of: Neuroscience. Volume 294(2015)
• Page Start: 172
• Page End: 181
• Publication Date: 2015-05-21
• Subjects: 5-Aza 5-Aza-2′-deoxycytidine -- α-CTF α-C-terminal fragment -- β-CTF β-C-terminal fragment -- AD Alzheimer's disease -- APP amyloid precursor protein -- ASBI APP-selective BACE1 inhibitor -- Aβ β-amyloid -- BACE1 β-site amyloid precursor protein-cleaving enzyme 1 -- ChIP chromatin immunoprecipitation -- DMEM Dulbecco's modified Eagle's medium -- DNMT DNA methyltransferase -- EDTA ethylene diamine tetraacetic acid -- EGTA ethylene glycol bis (2-aminoethyl) tetraacetic acid -- ELISA enzyme-linked immunosorbent assay -- FBS fetal bovine serum -- GA galangin -- HDAC histone deacetylase -- IgG Immunoglobulin G -- PCR polymerase chain reaction -- PI propidium iodide -- TSA trichostatin A -- VPA valproic acid; Alzheimer's disease -- galangin -- histone acetylation -- DNA methylation -- β-site amyloid precursor protein-cleaving enzyme 1; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.02.054
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: Galangin could significantly reduce BACE1 expression and then significantly decrease exogenous Aβ1-42 levels. Histone deacetylation is involved in galangin-induced down-regulation of BACE1. This is the first research to study natural flavonoids' epigenetic modification on AD-related gene. Abstract: Alzheimer's disease (AD), the most common cause of dementia in aging people, is found to have a critical link with the deposition of β-amyloid (Aβ) in the brain. The inhibition of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), a key enzyme for Aβ production, is a promising target for AD therapy. In pursuit to find a potent inhibitor of BACE1, we identified galangin, a natural flavonoid, had a significant lowering effect on Aβ levels. Furthermore, a dramatic reduction of BACE1 at mRNA and protein levels was observed after galangin treatment. We further investigated whether epigenetic mechanisms, such as histone acetylation and DNA methylation, were involved in galangin-induced transcriptional regulation of BACE1 . Our data show that galangin induces a decrease of acetylated H3 in the BACE1 promoter regions through the up-regulation of endogenous HDAC1-mediated deacetylation, which is independent of DNA methylation status. The above findings suggest a novel mechanism for polyphenols' neuroprotective effect in neurodegeneration and galangin as a potential drug candidate for AD therapy.