1Medical Genetic Centre, Guangdong Women and Children Hospital, Guangzhou 510010, China
2Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou 510010, China
3School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
4Dongsheng Hospital of Guangzhou, 375 People’s Road, Guangzhou 510120, China
5Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Second Road, Guangzhou 510080, China

Abstract 

In our previous studies, significant hypermethylation of the sirtuin 1 (SIRT1) gene and demethylation of the β-amyloid precursor protein (APP) gene were found in patients with Alzheimer’s disease (AD) compared with the normal population. Moreover, the expression of SIRT1 was significantly decreased while that of APP was increased in AD patients. These results indicated a correlation of DNA methylation with gene expression levels in AD patients. To further investigate the epigenetic mechanism of gene modulation in AD, we used two epigenetic drugs, the DNA methylation inhibitor 5-aza-2′-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA), to treat human neuroblastoma SK-N-SH cells in the presence of amyloid β-peptide Aβ25–35(Aβ25–35). We found that DAC and TSA had different effects on the expression trends of SIRT1 and APP in the cell model of amyloid toxicity. Although other genes, such as microtubule-associated protein τ, presenilin 1, presenilin 2, and apolipoprotein E, were up-regulated after Aβ25–35 treatment, no significant differences were found after DAC and/or TSA treatment. These results support the evidence in AD patients and reveal a strong correlation of SIRT1/APP expression with DNA methylation and/or histone modification, which may help understand the pathogenesis of AD.

Keywords

Sirtuin 1, DNA methylationHistone modification, Alzheimer’s disease, Trichostatin A

[SpringerLink]