In our previous studies, significant hypermethylation of the sirtuin 1（SIRT1） gene and demethylation of the b-amyloid precursor protein（APP） gene were found in patients with Alzheimer＇s disease（AD） compared wit...In our previous studies, significant hypermethylation of the sirtuin 1（SIRT1） gene and demethylation of the b-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-20-deoxycytidine（DAC） and the histone deacetylase inhibitor trichostatin A（TSA）, to treat human neuroblastoma SK-N-SH cells in the presence of amyloid b-peptide Ab25-35（Ab25-35）. 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 s, presenilin 1, presenilin 2, and apolipoprotein E, were up-regulated after Ab25-35treatment, 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.展开更多
基金supported by the National Basic Research Development Program of China (2006cb500700)the National Natural Science Foundation of China (30470904 and 31401627)+3 种基金Guangdong Provincial Natural Science Foundation of China (2010B031600070 and 2015A030313066)Science and Technology Social Development Project of Guangdong Province (2008B030301320 and 2012B031800053)a Guangdong Provincial Science and Technology Project (2013B051000009)a Guangzhou Science and Technology Plan Application Basic Research Project (2012J410076)
文摘In our previous studies, significant hypermethylation of the sirtuin 1（SIRT1） gene and demethylation of the b-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-20-deoxycytidine（DAC） and the histone deacetylase inhibitor trichostatin A（TSA）, to treat human neuroblastoma SK-N-SH cells in the presence of amyloid b-peptide Ab25-35（Ab25-35）. 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 s, presenilin 1, presenilin 2, and apolipoprotein E, were up-regulated after Ab25-35treatment, 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.
